1. URINARY TRACT INFECTION MOHAMMED ALMAGHRABI,MD PEDIATRIC NEPHROLOGIST KING FAHAD SPECIALIST HOSPITAL, DAMMAM, SAUDI ARABIA

2. introduction In the past 30–50 years, the natural history of urinary tract infection (UTI) in children has changed as a result of the introduction of antibiotics and improvements in healthcare. This change has contributed to uncertainty about the most appropriate and effective way to manage UTI in children, and whether or not investigations and follow-up are justified.

3. introduction UTI is a common bacterial infection causing illness in infants and children. It may be difficult to recognise UTI in children because the presenting symptoms and signs are non-specific, particularly in infants and children younger than 3 years. Collecting urine and interpreting results are not easy in this age group, so it may not always be possible to unequivocally confirm the diagnosis.

4. prevalence varied by age, gender, race, and circumcision status. Uncircumcised male infants less than 3 months of age and females less than 12 months of age had the highest baseline prevalence of UTI. Prevalence in our area is not known yet.

5. prevalence overall prevalence of UTI was 7.0%. The pooled prevalence rates of febrile UTIs in females aged 0–3 months, 3–6 months, 6–12 months, and >12 months was 7.5%, 5.7%, 8.3%, and 2.1% respectively. Among febrile male infants less than 3 months of age, 2.4% of circumcised males and 20.1% of uncircumcised males had a UTI. UTI rates were higher among white infants 8.0% than among black infants 4.7%. Among older children (<19 years) with urinary symptoms, the pooled prevalence of UTI (both febrile and afebrile) was 7.8% Nader, etal Pediatr Infect Dis J 2008;27: 302–308)

6. Introduction

8. definitions Definition of acute pyelonephritis: All studies required a positive urine culture. The additional criteria required for diagnosis of acute pyelonephritis in childrenwithUTI varied between studies: Two studies required fever > 38°C ( Baker 2001;Hoberman 1999), six required fever and at least one additional clinical feature ( Bakkaloglu 1996; Carapetis 2001; Chong 2003; Grimwood 1988; Noorbakhsh 2004; Repetto 1984; Schaad 1998; Toporovski 1992). Seven studies required fever, clinical features and/or laboratory abnormalities (C-reactive protein, erythrocyte sedimentation rate, white blood count) ( Fischbach 1989; Francois 1997; Kafetzis 2000; Levtchenko 2001; Montini 2003; Pylkkänen 1981; Vigano 1992).

9. definitions Definition of acute pyelonephritis Seven studies required fever, clinical features and/or laboratory abnormalities (C-reactive protein, erythrocyte sedimentation rate, white blood count) ( Fischbach 1989; Francois 1997; Kafetzis 2000; Levtchenko 2001; Montini 2003; Pylkkänen 1981; Vigano 1992). Three studies required fever, clinical features and acuterenal parenchymal injury on DMSA scan ( Benador 2001; Neuhaus 2006; Vilaichone 2001). One study required fever withCTscan evidence of acute lobular nephronia (Cheng 2006)

10. defintions Cystitis and lower urinary tract infection : Cystitis is inflammation of the urinary bladder, usually caused by infection, which can occur alone or in conjunction with pyelonephritis Uncomplicated cystitis : lower urinary tract and occurs in older children (older than 2 years) or adolescents with no underlying medical problems or anatomic or physiologic abnormalities. Complicated cystitis : Complicated cystitis is associated with upper tract disease, multiple-resistant uropathogens, or hosts with special considerations such as malignancy, diabetes, anatomic or physiologic abnormalities, or an indwelling bladder catheter.

11. defintions Asymptomatic bactiuria : The term asymptomatic bacteriuria (ASB) refers to the presence of two consecutive clear-voided urine specimens both yielding positive cultures (≥105 cfu/ml) of the same uropathogen, in a patient without urinary symptoms The prevalence of ASB in full-term infants is less than 1% and in premature infants 3%. Male infants are more affected than female infants The prevalence of ASB in school-age girls is approximately 2% and about 5% of them have bacteriuria of some type by the age of 15

12. Clinical symptoms

13. RISK FACTORS poor urine flow history suggesting previous UTI or confirmed previous UTI recurrent fever of uncertain origin antenatally-diagnosed renal abnormality family history of vesicoureteric reflux (VUR) or renal disease constipation dysfunctional voiding enlarged bladder abdominal mass evidence of spinal lesion poor growth high blood pressure.

14. Diagnostic workup Urine testing: - nitrate -Leukocyte estrase -Urine bacteria -Urine WBC -Urine culture

15. Diagnostic workup Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation. Correlation with clinical presentation is essential. Whiting P etal BMC Pediatr. 2005 Apr 5;5(1):4Whiting P

16. Diagnostic workup

17. Indication for culture : infants and children who have a diagnosis of acute pyelonephritis/upper urinary tract infection in infants and children with a high to intermediate risk of serious illness infants and children under 3 years infants and children with a single positive result for leukocyte esterase or nitrite infants and children with recurrent UTI infants and children with an infection that does not respond to treatment within 24–48 hours, if no sample has already been sent when clinical symptoms and dipstick tests do not correlate.

18. Diagnostic workup Procalcitonin and pyelonephritis PCT is a polypeptide identical to the prohormone of calcitonin that has been described as a potential marker for biologic disease. PCT is a 116- amino acid propeptide of calcitonin that lacks hormonal activity. Plasma concentrations in healthy subjects, chronic inflammatory states, viral infections, and autoimmune disease are below 0.5 ng/mL. In moderate localized bacterial infection PCT ranges from 0.5 to 2, and in severe gram-negative bacterial infections with sepsis and multiorgan failure the level is found to be above 2 ng/mL

19. Diagnostic workup Benador N, Siegrist CA, Gendrel D, et al Pediatrics 1998; 102:1422– 1425. Smolkin V, Koren A, Raz R, et al. Pediatr Nephrol 2002; 17:409– 412. Pecile P, Miorin E, Romanello C, et al.Pediatrics 2004; 114:e249– e254. Gurgoze MK, Akarsu S, Yilmaz E, et alPediatr Nephrol 2005; 20:1445–1448. 15 Bigot S, Leblond P, Foucher C, et al.Arch Pediatr 2005; 12:1075– 1080;

20. Imaging studies

21. Imaging of the urinary tract following infection has several aims: (1)to localize infection, (2) to identify the presence of reflux, (3) to detect renal scarring, (4) to identify structural anomalies.

22. Imaging studies The previous guidelines for the investigation and management of childhood UTI in the UK, published by the Royal College of Physicians in 1991 recommended that: all children should undergo renal tract imaging after a first episode of confirmed UTI and gave age-related recommendations. However, these guidelines have been superseded by those published by the Royal College of Pediatrics and Child Health, based on the USA practice guidelines of the American Academy of Pediatrics

23. Imaging studies The USA guidelines recommend investigation of febrile children aged between 2 months and 2 years with initial UTI with urgent renal ultrasound and either micturating cysto-urethrography (MCUG) if there is no clinical response within 48 h of antimicrobial therapy. If there is good clinical response, then these investigations should be performed at the earliest convenient time.

24. Imaging studies Ultrasound : Hoberman etal nengl j med 348;3 nejm.january 16, 2003

25. Imaging studies Prenatal-RUS have been performed in most children 5 years old hospitalized with a first simple UTI. Concordance with post-infection tests is very high with positive predictive value of more than 96% Findings which appear only in post-infectious RUS usually have negligible effects on children’s management. Thus, in such children with normal antenatal RUS omitting post-UTI RUS could be considered Dan Miron etal Arch Dis Child 2007;92:502–504

26. Is this type of antenatal care existing in our community ….?

27. Imaging studies Hoberman etal nengl j med 348;3 nejm.january 16, 2003

28. Is it necessary to do VCUG as screening ?:

29. Imaging studies Preda prospectively studied 290 children younger than 1 year of age with a documented UTI using DMSA scintigraphy and VCUG to detect VUR. Only 1 child of 141 with a normal DMSA scan had VUR grade III or higher. The positive and negative predictive values for DMSA scintigraphy to detect higher grade VUR were 17% and 99% respectively. Thus, a negative DMSA scan may help to rule out VUR but is not diagnostic if positive. Preda I, et al. J Pediatric. 2007;151:581–584, e1.

30. Imaging studies So, what happens if we miss vesicouretric reflux (VUR) ??......

31. Imaging studies The natural history for lower grades of VUR (grades I,II, and III) is spontaneous resolution at a rate of 13% per year There are recent data to support the notion that mild and moderate VUR do not increase the incidence of UTI pyelonephritis or renal scarring after acute pyelonephritis VUR, even if dilated, does not seem to cause renal scarring in the postnatal period. VUR is related to congenital renal damage and to the development of upper tract UTI but has not been shown to cause postnatal kidney damage without infection

32. Imaging studies DMSA : A DMSA scan performed during an episode of suspected acute pyelonephritis is the gold standard to localize the site of infection. As clinical symptoms are often nonspecific, imaging tests can be useful in confirming or excluding the diagnosis. Several authors have shown that one in three patients with a clinically suspected acute pyelonephritis have a normal DMSA Jacobsson B ETAL Arch Dis Child 67:1338-1342, 1992 18. Levtchenko et al Pediatr Nephrol 16: 878-884, 2001

33. Imaging studies The DMSA scan performed during the acute pyelonephritis appears to have prognostic value. It has been shown that a normal DMSA during an acute pyelonephritis with or without reflux is associated with a 0% risk of renal scarring. Mild renal inflammatory involvement with or without reflux and extensive renal involvement without reflux are likely to be associated with an intermediate risk of developing renal scars after the UTI. Extensive renal inflammatory involvement with reflux is associated with a high risk of developing renal scars.20 Biggi A,et al: Pediatr Nephrol 16:733-738, 2001

34. Imaging studies Incidence of scarring : Among 23 references the overall rates of renal scarring in terms of patients and renal units were 41.6% and 37.0%, respectively. In terms of patients the incidence of renal scarring following acute pyelonephritis varied by region, from 26.5% (Australia) to 49.0% (Asia). In terms of renal units the incidence of acquired renal cortical scarring varied by region, from 16.7% (Middle East) to 58.4% (Asia). When combined by vesicoureteral reflux status children and renal units with refluxing ureters exhibited an increased risk of renal scarring (odds ratios 2.8 and 3.7, William C.etal Journal of urology Vol. 181, 290-298, January 2009

35. Traditional Imaging Strategies in Children With UTI Approach: The Focus on Reflux This strategy is focused on VUR as the main risk factor in children with UTI. Children with VUR are considered at high risk of developing renal damage and therefore they should be identified with a cystogram and commenced on prophylactic antibiotics until the VUR resolves.

36. Traditional Imaging Strategies in Children With UTI this approach selects a number of children who are not at risk of renal scarring and fails to identify other children, with no demonstrable VUR, who nevertheless do develop renal scarring. Moreover, the MCUG is perceived as traumatic and invasive test, especially in older children, with an additional associated risk of infection.

37. Aggressive intervention to avoid presumed serious complications

38. Coasty procedures Extra burden on healthy children and their families Questionable chronic complications

39. the compliance of practitioners with the AAP guidelines is startlingly low. In the state of Washington, a large survey of children who experienced UTI in the first year of life showed that only 35% received imaging according to the AAP guidelines, while 51% received recommended antimicrobial prophylaxis. Cohen AL, et al. Pediatrics. 2005;115:1474 –1478.

40. New Imaging Strategies in Children With UTI A New Approach: The Focus on Acute Renal Inflammatory Involvement This is focused on detecting renal inflammatory involvement during the clinical episode of acute pyelonephritis and uses the acute DMSA, performed during the episode of infection, as its cornerstone. Hansson S, et al:J Urol 172:1071-1073, 2004

41. National institute for health and clinical excellence

44. Acute management

45. Questions to be addressed : Inpatient vs outpatient? Oral vs intravenous ? First line therapy ? Therapy duration?

46. Acute management Decision to hospitalize: Age <2 months Clinical urosepsis or potential bacteremia Immunocompromised patient Vomiting or inability to tolerate oral medication Lack of adequate outpatient follow-up (eg, no telephone, live far from hospital, etc.) Failure to respond to outpatient therapy

47. Acute management

48. The following implications for practice in the treatment of children with acute pyelonephritis have been identified: There are no significant differences in efficacy between treatment with oral cefixime, ceftibuten or amoxicillin/ clavulanic acid given for 10 to 14 days and IV therapy given for three days followed by oral therapy for a total duration of 10 to 14 days suggesting that children with acute pyelonephritis can be treated effectivelywith oral antibiotics. There are no significant differences in efficacy between IVantibiotic therapy given for two to four days followed by oral therapy with total therapy duration of 10 to 21 days and IV antibiotic therapy given for 7 to 10 days with total duration of therapy of 10 to 21 days.

49. Acute management The optimal duration of initial IV antibiotic therapy is unknown. Studies using comparing oral with IV then oral antibioticsor IV then oral with IV therapy were no stratified according to the grade of vesicoureteric reflux so it remains unclear whether results apply to children with dilating vesicoureteric reflux.

50. Acute management Single daily dosing of aminoglycosides is safe and effective compared with eight-hourly dosing. No data are available as to whether aminoglycosides alone or in combination are as effective as other medications including third generation cephalosporins in initial parenteral treatment.

51. Acute management Implications for research IN treatment of pyelonephritis: Further RCTs are required to determine the benefits and harms in children of different ages with acute pyelonephritis of: Treatment for shorter periods (seven days or less) compared with 10 to 14 days. Initial treatment with oral antibiotics compared with parenteral therapy or IV then oral therapy compared with IV therapy in children with dilating VUR or other major urinary tract malformation.

52. Acute management Management of cystitis : - complicated cystitis -uncomplicated cystitis

53. ASYMPTOMATIC BACTERURIA

54. Prevention

55. Antibiotics prophylaxis The recommendation of prophylactic antimicrobial therapy is based on the following premises: coexisting vesicoureteral reflux predisposes children with urinary tract infections to the development of acute pyelonephritis; reflux nephropathy, which leads to renal scarring, is a consequence of infection plus reflux; continuous prophylactic antimicrobial herapy successfully prevents infection until reflux resolves spontaneously or is corrected surgically; the initiation of treatment after the diagnosis of intercurrent episodes of urinary tract infection in such children will be insufficient to prevent scarring.

56. Antibiotics prophylaxis

57. Antibiotic prophylaxis

58. Antibiotics prophylaxis

60. CONCLUSIONS. After 1 year of follow-up monitoring, mild/moderate VUR does not increase the incidence of UTI, pyelonephritis, or renal scarring after acute pyelonephritis. Moreover, a role for urinary antibiotic prophylaxis in preventing the recurrence of infection and the development of renal scars is not supported by this study. Garin EH, et al.Pediatrics. 2006;117:626–632.

61. Antibiotics prophylaxis Interventions for primary vesicoureteric reflux (Review) Hodson EM, Wheeler DM, Smith GH, Craig JC, Vimalachandra D 2009, Issue 1

62. Antibiotics prophylaxis Eleven studies (1148 children) were identified. Seven compared correction of VUR (by surgery or endoscope) plus antibiotics for 1-24 months with antibiotics alone, two compared antibiotics with no treatment and two compared different materials for endoscopic correction of VUR.

63. Antibiotics prophylaxis Risk of UTI by 2, 5 and 10 years was not significantly different between surgical and medical groups Combined treatment resulted in a 50% reduction in febrile UTI by 10 years,but no concomitant reduction in risk of new or progressive renal damage by 10 years Authors’ conclusions: It is uncertain whether the treatment of children with VUR confers clinically important benefit. The additional benefit of surgery over antibiotics alone is small at best

64. THERE ARE NO EXISTING STUDIES TESTING FOR EFFICACY OF ANTIBIOTICS PROPHYLAXIS IN HIGH GRADE REFLUX

65. Other preventive measures CULTURE SURVILLANCE AVOIDANCE BUBBLE PATH CRANBERRY JUICE CRCUCISSION

66. Summary of new advances Imaging studies shifted toward more targeted objective DMSA has 99%-ve predictive value for VUR Scarring related mainly to both inflammation and reflux Accumilating evidence of no rule of antibiotics prophylaxis in grade I, II,III reflux No evidence in high grade reflux

67. WHERE IS OUR GUIDELINES DIRECTION ?

68. OUR PROBLEMS Antenatal care problems Weak intact health system Antibiotics abuse Underestimation of problems Lacking of epidimiological studies

69. Urinary symptoms without four -Ve test Non specific symptoms Urinary symptoms Febrile Child + test without symptoms Start Antibiotic Consider ImagineProphylaxes No UTI Presume UTI + test Do Culture Do tests Do culture

70. TAKE HOME MESSAGE UTI is high index of suspicion in all febrile children less than 3 years Identifying risk group is an essential part of management Urine culture still is the gold standard of diagnosis and should be considered before any antibiotics therapy U.S is needed for all definite UTI patient in our population Antibiotic prophylaxis is considered for high risk group only

71. THANK YOU

72. urinary symptoms without fever - either no or low grade fever - if positive tests …..consider cystitis - treat with oral antibiotics for 3 to 5 days Back

73. Positive tests without symptoms -Consider asymptomatic bactiuria -No antibiotic treatment -Consider conservative treatment Back

74. Antibiotic therapy I.V therapy for : - less than 3 months - atypical UTI Therapy duration ; - pyelonephritis n 7-10 days complicated infections :at least 2 weeks - cystitis : 3 to 5 days Back

75. Imaging evaluation U.S kidney and urinary tract for all treated patient VCUG for those with abnormal U.S and those with atypical UTI DMSA for every difinite UTI after 4 months DMSA in acute episode for complicated UTI and if diagnosis is uncertin Back

76. Antibiotic prophylaxis It is considered for every abnormal VCUG with grade III,IV, V VUR It may be considered in atypical UTI Back