The changing resistance patterns of bacterial uropathogens in children.

BACKGROUND: Increased antimicrobial resistance is a problem in managing urinary tract infections (UTI). With this study we assessed the resistance patterns of urinary isolates in children with UTI between January 2017 and January 2018. METHODS: A retrospective cohort study was conducted. Among 5,443 isolates, a total of 776 UTI episodes in 698 patients were included. Patients' gender, age, voiding dysfunction, UTI history, prophylaxis status, and presence of vesicoureteral reflux were noted. Patients were divided into three age groups: group 1 for ages ≤12 months; group 2 for ages 13-60 months; and group 3 for ages >60 months. The susceptibilities of etiologic agents to different antimicrobials were explored. RESULTS: Median age was 54 months (range 1 month-21 years); male to female ratio was 1:5. The most common causative agent was Escherichia coli (83% of the cases), followed by Klebsiella pneumoniae (7.5%). Resistance to ampicillin (62.6%) and co-trimoxazole (39.8%) were remarkable in all isolates. Overall extended-spectrum beta-lactamase (ESBL) positivity was 23.5%. The highest resistance rates, higher ESBL positivity (28.6%), and K. pneumoniae frequency (13.5%) were observed in group 1. Ceftriaxone resistance was significantly low (0.5%) in the ESBL (-) group, which constituted the majority of the isolates. Higher resistance rates were observed among the patients on prophylaxis compared to those off prophylaxis (P < 0.001). CONCLUSION: Ceftriaxone can still be used for empirical treatment; however, initial urine culture results are crucial due to high ESBL positivity. Special consideration must be taken for patients under 1 year of age. Periodical surveillance studies are needed to explore the changing resistance patterns of uropathogens and modify treatment plans.

Uropathogen Resistance and Antibiotic Prophylaxis: A Meta-analysis.

CONTEXT: Limited data exist regarding uropathogen resistance in randomized controlled trials of urinary tract infection (UTI) prevention and antibiotic prophylaxis. OBJECTIVE: To assess the effect of prophylaxis on developing a multidrug-resistant first recurrent UTI among children with vesicoureteral reflux. DATA SOURCES: Cochrane Kidney and Transplant Specialized Register through May 25, 2017. STUDY SELECTION: Randomized controlled trials of patients ≤18 years of age with a history of vesicoureteral reflux being treated with continuous antibiotic prophylaxis compared with no treatment or placebo with available antibiotic sensitivity profiles. DATA EXTRACTION: Two independent observers abstracted data and assessed quality and validity per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Adjusted meta-analyses were performed by using a mixed-effects logistic regression model. RESULTS: One thousand two hundred and ninety-nine patients contributed 224 UTIs. Patients treated with prophylaxis were more likely to have a multidrug-resistant infection (33% vs 6%, P < .001) and were more likely to receive broad-spectrum antibiotics (68% vs 49%, P = .004). Those receiving prophylaxis had 6.4 times the odds (95% confidence interval: 2.7-15.6) of developing a multidrug-resistant infection. One multidrug-resistant infection would develop for every 21 reflux patients treated with prophylaxis. LIMITATIONS: Variables that may contribute to resistance such as medication adherence and antibiotic exposure for other illnesses could not be evaluated. CONCLUSIONS: Prophylaxis increases the risk of multidrug resistance among recurrent infections. This has important implications in the risk-benefit assessment of prophylaxis as a management strategy and in the selection of empirical treatment of breakthrough infections in prophylaxis patients.

Emerging Landscape of Antibiotic Resistance and Use of Endoscopic Injection in Vesicoureteral Reflux.

Vesicoureteral reflux (VUR) in children is often treated with antimicrobials for prolonged durations, which often leads to antimicrobial resistance. In this context, this review article discusses the use of endoscopic injection in VUR as a safe and efficacious option for these children. The literature pertaining to VUR- its clinical manifestation and management, antibiotic resistance- with special reference to management of VUR, and endoscopic dextranomer/hyaluronic acid gel injection for management of VUR was reviewed by identifying key words in a PubMed search. Vesicoureteral reflux is managed using antibiotic prophylaxis, urotherapy, or surgical correction (open, endoscopic injection therapy, or laparoscopic). Continuous antibiotic prophylaxis for urinary tract infections in VUR can lead to antibiotic resistance. Urotherapy cures about 75% of cases with dysfunctional voiding and the rest have to be managed at specialized centers. While open surgery provides relief of VUR and related complications in majority, it requires hospitalization. Endoscopic injection of dextranomer/hyaluronic acid gel into the submucosa of bladder or ureter near ureteral orifice increases the tissue bulk and creates a valve function. Various studies show the efficacy and safety of endoscopic injection of dextranomer/hyaluronic acid gel in VUR. The use of endoscopic injection being a non-invasive modality, can be performed in children with VUR in the outpatient department, precluding hospitalization. In view of the threat of developing antimicrobial resistance and also realising the need for definitive treatment of VUR, endoscopic injection is an efficacious and safe option in primary VUR.

Urinary tract infection in small children: the evolution of renal damage over time.

BACKGROUND: Our objective was to analyze the evolution of kidney damage over time in small children with urinary tract infection (UTI) and factors associated with progression of renal damage. METHODS: From a cohort of 1003 children <2 years of age with first-time UTI, a retrospective analysis of 103 children was done. Children were selected because of renal damage at index 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy at least 3 months after UTI, and a late DMSA scan was performed after at least 2 years. Damage was classified as progression when there was a decline in differential renal function (DRF) by ≥4%, as regression when there was complete or partial resolution of uptake defects. RESULTS: Of 103 children, 20 showed progression, 20 regression, and 63 remained unchanged. There were no differences between groups regarding gender or age. In the progression group, 16/20 (80%) children had vesicoureteral reflux (VUR) grade III-V and 13 (65%) had recurrent UTI. In multivariable regression analysis, both VUR grade III-V and recurrent UTI were associated with progression. In the regression group, 16/20 (80%) had no VUR or grade I-II, and two (10%) had recurrent UTI. CONCLUSIONS: Most small children with febrile UTI do not develop renal damage and if they do the majority remain unchanged or regress over time. However, up to one-fifth of children with renal damage diagnosed after UTI are at risk of renal deterioration. These children are characterized by the presence of VUR grades III-V and recurrent febrile UTI and may benefit from follow-up.

Profilaxis antibiótica en los pacientes con reflujo vesico-ureteral grado III / Antibiotic prophylaxis in patients with grade III vesicoureteral reflux

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[Urinary tract infections in children]. / Harnwegsinfekte bei Kindern.

Urinary tract infections (UTI) are the most common bacterial infections in children. The symptoms are not very specific and range from abdominal pain, poor feeding to nocturnal urinary incontinence. The technique of collecting urine plays an important role for securing the diagnosis. The best way to obtain urine in non-toilet-trained children is catheterization or suprapubic bladder aspiration. In toilet-trained children midstream urine is an acceptable alternative after cleaning the foreskin or labia. In the case of an infection a prompt empirical antibiotic therapy is necessary to reduce the risk of parenchymal scarring of the kidneys. There are different approaches to diagnose vesicoureteral reflux in different countries. The commonly used standard approach in Germany is voiding cystourethrography. In the case of reflux dimercaptosuccinic acid (DMSA) scintigraphy should be performed additionally to exclude renal scarring (bottom-up approach).

Flushing of the vagina and the prepuce-a cause for contaminated urine cultures in children.

OBJECTIVE: An uncontaminated urine culture is a prerequisite for the diagnosis of a urinary tract infection. However, this may be difficult to obtain in small children. We have studied the frequency of ballooning of the prepuce in non-circumcised boys and vaginal reflux in girls during voiding as a possible cause of contaminated urine cultures. METHODS: All micturating cystourethrograms (MCUG) performed in our institution over the last 5 years in children aged 0-15 years were reviewed retrospectively for ballooning of the foreskin or vaginal reflux as a potential source of bacterial contamination. The voiding pictures were routinely done with the catheter present for the first voiding cycle and then removed on the second void. RESULTS: A total of 526 children (77.4 % boys, 22.6 % girls) were eligible for the study. Ballooning of the foreskin was identified on the micturition pictures of 115 (38 %) boys, with the frequency significantly higher in boys aged <12 months [odds ratio (OR) 4.1; 95 % confidence interval (CI) 2.1-7.3)] and boys with vesicoureteral reflux (OR 1.6; 95 % CI 1.06-2.4). Seventeen girls (14.3 %) showed vaginal reflux. No correlation with age or vesicoureteral reflux was found in the girls. CONCLUSION: Ballooning of the prepuce or vaginal reflux was seen on a fluoroscopic MCUG in a large proportion of children during their voiding. This normal phenomenon might cause contaminated urine cultures when the urine is obtained by bag or clean catch.

Inflammation drives renal scarring in experimental pyelonephritis.

Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis.

Predictors of Antimicrobial Resistance among Pathogens Causing Urinary Tract Infection in Children.

OBJECTIVE: To determine which children with urinary tract infection are likely to have pathogens resistant to narrow-spectrum antimicrobials. STUDY DESIGN: Children, 2-71 months of age (n = 769) enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux or Careful Urinary Tract Infection Evaluation studies were included. We used logistic regression models to test the associations between demographic and clinical characteristics and resistance to narrow-spectrum antimicrobials. RESULTS: Of the included patients, 91% were female and 76% had vesicoureteral reflux. The risk of resistance to narrow-spectrum antibiotics in uncircumcised males was approximately 3 times that of females (OR 3.1; 95% CI 1.4-6.7); in children with bladder bowel dysfunction, the risk was 2 times that of children with normal function (OR 2.2; 95% CI 1.2-4.1). Children who had received 1 course of antibiotics during the past 6 months also had higher odds of harboring resistant organisms (OR 1.6; 95% CI 1.1-2.3). Hispanic children had higher odds of harboring pathogens resistant to some narrow-spectrum antimicrobials. CONCLUSIONS: Uncircumcised males, Hispanic children, children with bladder bowel dysfunction, and children who received 1 course of antibiotics in the past 6 months were more likely to have a urinary tract infection caused by pathogens resistant to 1 or more narrow-spectrum antimicrobials.

Urinary tract infection in infants: the significance of low bacterial count.

BACKGROUND: In national guidelines for urinary tract infection (UTI) in children, different cut-off levels for defining bacteriuria are used. In this study, the relationship between bacterial count in infant UTI and inflammatory parameters, frequency of vesicoureteral reflux (VUR), kidney damage, and recurrent UTI was analyzed. METHODS: We conducted a population-based retrospective study of 430 infants age <1 year with symptomatic UTI diagnosed by suprapubic aspiration. Clinical and laboratory parameters, findings on voiding cystourethrography and (99m)technetium dimercapto-succinic acid scintigraphy, and frequency of recurrence were related to bacterial count at the index UTI. RESULTS: Eighty-three (19%) infants had bacterial counts <100,000 colony-forming units (CFU)/ml and 347 (81%) had ≥100,000 CFU/ml. There was similar frequency of VUR (19% in both groups), kidney damage (17 and 23%, p = 0.33) and recurrent UTI (6 and 12%, p = 0.17) in the low and high bacterial group. Non-E. coli species were more prevalent (19 versus 6%, p = 0.0006) and mean C-reactive protein was lower (50 vs. 79 mg/l, p <0.0001) in the low bacteria group. CONCLUSIONS: UTI with low bacterial count is common and of importance since it may be associated with VUR and renal damage. Non-E. coli species and low inflammatory response were more prevalent in UTI with low bacterial count.

Escherichia coli virulence patterns may help to predict vesicoureteral reflux in paediatric urinary tract infections.

AIM: Ultrasound and biological tools are used to predict high-grade vesicoureteral reflux, but other markers are needed to better select patients who need voiding cystography. Our aim was to determine whether studying Escherichia coli virulence factors would help to predict vesicoureteral reflux in patients with their first acute pyelonephritis. METHODS: We included children presenting with E. coli-related acute pyelonephritis or cystitis. Vesicoureteral reflux was assessed by voiding cystography. Virulence factors were identified by multiplex polymerase chain reaction. Statistical analysis was performed using logistic regression and the mean c-statistic test. RESULTS: We included 198 patients: 30 with cystitis and 168 with acute pyelonephritis, including 46 with vesicoureteral reflux. High-grade reflux was associated with acute pyelonephritis caused by the E. coli lacking virulence factors papGII (82% versus 47%, p < 0.001) or papC (85% versus 53%, p < 0.001) or belonging to phylogenetic group A or B1. When we added genetic data (lack of papGII, fyuA and phylogenetic groups) to classical predictors of vesicoureteral reflux (ultrasound examination, gender, age), the ability to predict high-grade reflux increased, with the c-statistic rising from 0.88 to 0.93. CONCLUSION: Bacterial virulence factors and clinical factors helped to predict high-grade reflux and may help to avoid unnecessary voiding cystographies.

Profile of urinary tract infections in paediatric patients.

BACKGROUND & OBJECTIVES: This cross-sectional study was conducted at a tertiary care centre in Puducherry, south India, with the aim of finding the profile of the paediatric urinary tract infection (UTI), bacterial pathogens involved, and also to observe vesicoureteric reflux (VUR) and renal scarring in these patients. METHODS: A total of 524 paediatric patients ≤13 yr, suspected to have UTI, were included in the study. Urine samples were collected, processed for uropathogen isolation and antibiotic susceptibility test was performed as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. Thirty two culture proven children with UTI underwent micturating cysto-urethrography (MCU) and dimercaptosuccinic acid (DMSA) scanning was done for 69 children. RESULTS: o0 f the 524 children, 186 (35.4%) had culture proven UTI with 105 (56.4%) being infants, 50 (27.4%) between 1-5 yr, 30 (16.12%) between 5-13 yr and 129 (69.35%) males. Posterior urethral valve (PUV) was noted in three, hydronephrosis in one, VUR in 18 and renal scarring in 33. VUR as well as renal scarring were more in males >1 yr of age. A significant association (P=0.0054) was noted with a combined sensitivity and specificity of these investigations being 83 and 90 per cent, respectively of the MCU and DMSA scans for detecting VUR. Escherichia coli was the most common pathogen isolated, sensitive to nitrofurantoin, followed by cefoperazone-sulbactam, aminoglycosides and meropenem. INTERPRETATION & CONCLUSIONS: Our results indicate that UTI varies with age and gender and extensive evaluation is required in boys over one year of age with UTI. This study also highlights the better efficacy of aminoglycosides, cefoperazone-sulbactam and nitrofurantoin in vitro compared with meropenem in Gram-negative uropathogens.

Consequences of following the new American Academy of Pediatrics guidelines for imaging children with urinary tract infection.

OBJECTIVE: Urinary tract infections (UTIs) and vesicoureteral reflux (VUR) are assumed to predispose children to renal damage. Awareness of the significance of VUR and the possibility of reducing UTI recurrence and renal damage has warranted guidelines on which patients should undergo imaging after UTI. An authoritative guideline has been issued by the American Academy of Pediatrics (AAP). This study assessed the applicability of the AAP guidelines to a subpopulation of patients with UTI, 2-24-month-old children with febrile UTI. MATERIALS AND METHODS: The records of 394 children aged 2-24 months with their first UTI were reviewed. Data were recorded on the indications for renal and bladder ultrasonography (RBUS) and voiding cystourethrography (VCUG) according to the AAP guidelines, RBUS results, VCUG results, use of antimicrobial prophylaxis, antireflux procedures and other urological treatment, and UTI recurrence. RESULTS: An indication for RBUS was seen in 344 patients. RBUS results were abnormal in 87, including 53 with urinary tract dilatation. An unnecessary RBUS would have been avoided in 43 patients. Seven patients with an abnormal RBUS would not have undergone RBUS. An indication for VCUG was seen in 126 patients. VCUG was performed in 206 patients; VUR was found in 72 patients, including 36 with high-grade VUR. An unnecessary VCUG would have been avoided in 82 patients. High-grade VUR would have been missed in six patients. Five patients would not have undergone surgery. CONCLUSION: The AAP guidelines for imaging studies in children aged 2-24 months with febrile UTI seem applicable to clinical practice.

Staphylococcus aureus urinary tract infections in children are associated with urinary tract abnormalities and vesico-ureteral reflux.

BACKGROUND: Staphylococcus aureus is an uncommon cause of pediatric urinary tract infection (UTI). Data regarding urinary tract malformations in children with S. aureus UTI is limited. METHODS: The medical records of all children aged 0 to 16 years at Shaare Zedek Medical Center between 2001 and 2013 and who were diagnosed with S. aureus UTI were reviewed for demographic, clinical, and laboratory data. Patients with Escherichia coli UTIs during the same period were included as controls. RESULTS: S. aureus was the cause of UTI in 26 children, of whom six were bacteremic. Compared to children with E. coli UTI, children with S. aureus had higher rates of abnormal findings in ultrasound (77 vs. 22%; p < 0.001). Similarly, more patients with S. aureus UTI had abnormal voiding cystourethrogram (53 vs. 23%; p < 0.001) or vesicoureteral reflux (50 vs. 23%; p < 0.001). The median duration of hospitalization for patients with S. aureus UTI was significantly longer than for patients with E. coli UTI (8 vs. 2.3 days; p = 0.0003). CONCLUSIONS: S. aureus is an uncommon urinary pathogen among children. The finding of S. aureus UTI requires thorough search for urinary abnormalities.

Does prompt treatment of urinary tract infection in preschool children prevent renal scarring: mixed retrospective and prospective audits.

OBJECTIVE: To test whether active management of urinary tract infections (UTI) in young children by general practitioners can reduce kidney scarring rates. DESIGN: A comparison of two audits in Newcastle, of children aged <8 years, presenting with UTIs ; a retrospective audit of conventional management during 1992-1995 (1990s) versus a prospective audit of direct access management during 2004-2011 (2000s). MAIN OUTCOME MEASURES: Kidney scarring rates, and their relationship with time-to-treat. RESULTS: Children with a first UTI in the 2000s compared to those in the 1990s, were referred younger, were half as likely to have a renal scar (girls OR 0.47, 95% CI 0.29 to 0.76; boys 0.35, 0.16 to 0.81), and were about 12 times more likely to have vesicoureteric reflux without scarring (girls 11.9, 4.3 to 33.5; boys 14.4, 4.3 to 47.6). In the 2000s, general practitioners treated about half the children at first consultation. Children who were treated within 3 days of their symptoms starting were one-third as likely to scar as those whose symptoms lasted longer (0.33, 0.12 to 0.72). INTERPRETATION: Most kidney defects seen in children after UTIs, are acquired scars, and in Newcastle, active management in primary care has halved this rate.

Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice.

Vesicoureteric reflux (VUR) is a common congenital defect of the urinary tract that is usually discovered after a child develops a urinary tract infection. It is associated with reflux nephropathy, a renal lesion characterized by the presence of chronic tubulointersitial inflammation and fibrosis. Most patients are diagnosed with reflux nephropathy after one or more febrile urinary tract infections, suggesting a potential role for infection in its development. We have recently shown that the C3H mouse has a 100% incidence of VUR. Here, we evaluate the roles of VUR and uropathogenic Escherichia coli infection in the development of reflux nephropathy in the C3H mouse. We find that VUR in combination with sustained kidney infection is crucial to the development of reflux nephropathy, whereas sterile reflux alone fails to induce reflux nephropathy. A single bout of kidney infection without reflux fails to induce reflux nephropathy. The host immune response to infection was examined in two refluxing C3H substrains, HeN and HeJ. HeJ mice, which have a defect in innate immunity and bacterial clearance, demonstrate more significant renal inflammation and reflux nephropathy compared with HeN mice. These studies demonstrate the crucial synergy between VUR, sustained kidney infection and the host immune response in the development of reflux nephropathy in a mouse model of VUR.

[Procalcitonin, a useful biomarker in pediatric urinary tract infection]. / La procalcitonine : un marqueur utile pour l'enfant présentant une infection urinaire.

Urinary tract infections (UTIs) are one of the most common sources of bacterial infections among young febrile children. Accurate diagnosis of acute pyelonephritis (APN) and vesico-ureteral reflux (VUR) are important because of their association with renal scarring, sometimes leading to long-term complications. However, the gold standard examinations are either a DMSA scan for APN and scarring, or cystography for VUR, but both present limitations (feasibility, pain, cost, etc.). Procalcitonin, a reliable marker of bacterial infections, was demonstrated to be a good predictor of renal parenchymal involvement in the acute phase and in late renal scars, as well as of high-grade VUR. These findings need further broad validations and impact studies before being implemented into daily practice. However, procalcitonin may play a role in the complex and still debated picture of which examination should be performed after UTI in children.

Predicting factors of breakthrough infection in children with primary vesicoureteral reflux.

PURPOSE: Many pediatric urologists still favor using prophylactic antibiotics to treat children with vesicoureteral reflux (VUR). However, breakthrough infection sometimes occurs, leading to significant increases in morbidity as a result of renal scarring. Therefore, we tested whether abnormal renal scan and other factors are predictive of breakthrough infection using univariate analyses. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 163 consecutive children who were diagnosed with vesicoureteral reflux between November 1997 and June 2010. Clinical parameters for the statistical analysis included form of presentation, gender, age, VUR grade, laterality, presence of intrarenal reflux, class of antibiotic drug, and presence of abnormal renal scan by Dimercapto-succinic acid. Clinical parameters used for prognostic factors were established by univariate analyses. Fisher's exact test and unpaired t-test were done using SPSS software [SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA)]. RESULTS: Breakthrough infection developed in 61 children (48.0%). A total of 58 children (45.7%) had abnormal renal scans. Time to development of breakthrough infection was significantly longer in girls (9.0±8.2 months) than in boys (5.8±4.8 months, p<0.05). On univariate analysis, though statistically not significant, the most predictive factor of breakthrough infection was abnormal renal scan (p=0.062). In patients with abnormal renal scans, breakthrough infection was not associated with mode of presentation, gender, grade or prophylactic antibiotics. However, there was a significant difference between patients younger than 1 year and those 1 year old or older. Mean±SD age at diagnosis of VUR in patients with breakthrough infection (1.14±3.14) was significantly younger than in those without breakthrough infection (5.05±3.31, p=0.009). There was also a significant difference between patients with bilateral or unilateral reflux (p=0.028). CONCLUSION: Our data showed that abnormal renal scan was the most predictive factor of breakthrough infection and demonstrated statistical significance in patients under the age of 1 year. Parents and physicians should remain aware that these patients are at high risk of breakthrough urinary tract infection, which may potentially lead to renal damage.