P. Brandstrom has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

P. Brandstrom has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

Prophylaxis or not? Per Brandström Queen Silvia Children s Hospital Gothenburg Per Brandström ESPN 2015 Brussels 2

Prophylaxis Prevent recurrent UTI further renal damage In children at risk Per Brandström ESPN 2015 Brussels 3

UTI in children UTI first 6 years of life 8 % of girls 2 % of boys Asymptomatic bacteriuria Often combined with bladder dysfunction Urethritis Cystitis Pyelonephritis Per Brandström ESPN 2015 Brussels 4

UTI first 2 years of life Swedish UTI study 1993-95 Jakobsson et al (1999) Pediatrics 104:222 226 Per Brandström ESPN 2015 Brussels 5

UTI recurrence Recurrence rate 20-40% 2/3 symptomatic Winberg et al, Kidney int Suppl 1975;4:S101-6 Nuutinen and Uhari, Pediatr Nephrol 2001;16:69-72 Per Brandström ESPN 2015 Brussels 6

Symptomatic UTI Discomfort and distress..nasty, short-term, acute illness prone to recurrence Risk of renal damage new scars progression of existing parenchymal defects Long term consequences Renal deterioration Hypertension Pregnancy complications End stage renal disease Wennerström et al, Arch Pediatr Adolesc Med 2000;154: 339-45 Gebaäck et al, Pediatr Nephrol 2015;30:1493-9 Craig and Williams, Pediatrics 2011;128: 984-5 Per Brandström ESPN 2015 Brussels 7

Risk factors for UTI Deranged preputial or periurethral commensal bacterial flora antibiotic treatment Vesicoureteral reflux dilating Dilatation of urinary tract hydronephrosis, megaureter prenatal screening Obstruction of urine flow dilatation residual urine Incomplete bladder emptying neurogenic bladder congenital abnormalities obstruction Per Brandström ESPN 2015 Brussels 8

Who s the enemy Escherichia coli the predominant pathogen Adhesion to urinary tract epithelium > 90% of primary UTI in girls > 80% in boys preputial area colonized by non-e. coli Gram negative bacteria (uncircumcised boys) Non-E. coli Klebsiella, Proteus, Enterobacter, Enterococci, Pseudomonas, Hemophilus infl, Staphylococci, GBS Per Brandström ESPN 2015 Brussels 9

Non-E. coli UTI More often urinary tract abnormalities Secondary to invasive procedures indwelling catheters antibiotic treatment for other causes Recurrent UTI Per Brandström ESPN 2015 Brussels 10

Resistant bacteria Intrinsic or natural resistance anaerobes to aminoglycosides Gram-negative bacteria against vancomycin Acquired resistance Mutations E. Coli chromosomal gene specifying dihydrofolate reductase where trimethoprim exerts it s effect Plasmids/horizontal gene transfer Vancomycin resistant enterococci reducing affinity to vancomycin Per Brandström ESPN 2015 Brussels 11

Multiresistant bacteria Extended Spectrum Beta-Lactamase ESBLcarba Transmitted by plasmids between species Meticillin Resistant Staph Aureus Vancomycin Resistant Enterococci Per Brandström ESPN 2015 Brussels 12

Proportion (%) resistant E. coli from urine cultures % Per Brandström ESPN 2015 Brussels 13

UTI, VUR and renal scarring Strong correlation between febrile UTI dilating vesicoureteral reflux (VUR) renal scarring Sex difference Boys congenital abnormalities Girls scarring from infections Per Brandström ESPN 2015 Brussels 14

VUR and prophylaxis Antibiotic prophylaxis to children with VUR Introduced in the 1960s to reduce UTI recurrence and subsequent scarring It became common practice to use prophylaxis for children with VUR other urinary tract abnormalities This policy has been challenged lack of scientific support concern about resistance Per Brandström ESPN 2015 Brussels 15

Opinions on prophylaxis No benefit from prophylaxis normal urinary tracts non-dilating VUR Indication for prophylaxis dilating VUR awaiting spontaneous resolution young children? After the first year of life boys have very few recurrences and do not benefit from prophylaxis girls with dilating VUR more prone to recurrences benefit from prophylaxis Per Brandström ESPN 2015 Brussels 16

Prophylaxis to children with VUR Hadjipanis A et al. Arch Dis Child 2015;100:341-347 Per Brandström ESPN 2015 Brussels 17

Recommendations on prophylaxis National Institute of Clinical Excellence NICE guidelines available at http://www.nice.org.uk/guidance/cg54 American Academy of Pediatrics Roberts et al, Pediatrics 2011;128;595-610 Italian Society of Pediatric Nephrology Ammenti et al, Acta Paediatr 2012;101:451-7 Canadian Paediatric Society Robinson et al, Paediatr Cild Health 2015;20:45-51 All rely on same studies Per Brandström ESPN 2015 Brussels 18

Randomized controlled studies Prophylaxis no treatment or placebo*. Garin Roussey-Kesler Pennesi Montini PRIVENT* Swe Refl Trial RIVUR* Nr of patients 218 225 100 338 576 203 607 Age inclusion 3m-17y 1m-7y 0-30 m 2m-7y 0-18y 1-2y 2m-5y Follow-up 1yr 1½yr 2yrs 1yr 1yr 2yrs 2yrs VUR 0-4 0-3 2-4 0-3?-5 3-4 1-4 Febr recurrence prophylaxis 9% 13% 36% 7% 7% 14% 15% no prophylaxis 3% 16% 30% 9% 13% 37% 27% Per Brandström ESPN 2015 Brussels 19

Prophylaxis of little or no value Garin Roussey-Kesler Pennesi Montini PRIVENT* Swe Refl Trial RIVUR* Nr of patients 218 225 100 338 576 203 607 Age inclusion 3m-17y 1m-7y 0-30 m 2m-7y 0-18y 1-2y 2m-5y Follow-up 1yr 1½yr 2yrs 1yr 1yr 2yrs 2yrs VUR 0-4 0-3 2-4 0-3?-5 3-4 1-4 Febr recurrence prophylaxis 9% 13% 36% 7% 7% 14% 15% no prophylaxis 3% 16% 30% 9% 13% 37% 27% at least in children with no or non-dilating VUR Montini subgroup VUR 3 fewer UTI on prophylaxis Per Brandström ESPN 2015 Brussels 20

Prophylaxis significant risk reduction Garin Roussey-Kesler Pennesi Montini PRIVENT* Swe Refl Trial RIVUR* Nr of patients 218 225 100 338 576 203 607 Age inclusion 3m-17y 1m-7y 0-30 m 2m-7y 0-18y 1-2y 2m-5y Follow-up 1yr 1½yr 2yrs 1yr 1yr 2yrs 2yrs VUR 0-4 0-3 2-4 0-3?-5 3-4 1-4 Febr recurrence prophylaxis 9% 13% 36% 7% 7% 14% 15% no prophylaxis 3% 16% 30% 9% 13% 37% 27% PRIVENT (Australia) reduction of absolute risk by 6% in all subcategories. RIVUR (USA) relative risk reduced by 50% (80% in children with BBD), also in children with VUR 1-2 Swedish Reflux Trial (VUR 3-4, infants not included) relative risk reduced by 67% in girls no reduction in boys Per Brandström ESPN 2015 Brussels 21

Time to first febrile recurrence RIVUR all children Swedish Reflux Trial girls only RIVUR Trial. N Engl J Med. 2014 Swedish Reflux Trial. J Urol. 2010 Per Brandström ESPN 2015 Brussels 22

Other reasons for prophylaxis Lack of scientific support Dilatation of urinary tract Obstruction of PUJ or VUJ Posterior urethral valve Neurogenic bladder dysfunction Voiding (bladder emptying) dysfunction Scientific support for no benefit Normal urinary tract after symptomatic UTI Urinary tract dilatation diagnosed prenatally Per Brandström ESPN 2015 Brussels 23

Negative effects of antibiotic prophylaxis High intestinal load of resistant bacteria Increased rate of UTI in children on CIC (Clean Intermittent Catheterization) Increased rate of UTI in children with VUR in some studies Selection of resistant bacteria Increased proportion of resistant bacteria in UTI Same number of UTI with resistant bacteria Per Brandström ESPN 2015 Brussels 24

Ideal prophylactic agent Active against uropathogenic bacteria Inhibitory concentration in urine Low selection of resistant bacteria Minimal impact on commensal flora in the bowel and periurethral area Enteric uptake in small intestine Lowest effective dose Minimal environmental effects No adverse effects Suitable for children Formula and taste Per Brandström ESPN 2015 Brussels 25

Trimethoprim High bioavailability High urine concentration Eliminates periurethral E. coli Leaves anaerobic microflora intact Selection of resistant strains Reports globally 15-85% resistance in E. coli Higher risk of adverse effects if combined with sulfamethoxazole Dose recommendations 0.5 to 2 mg/kg once daily Per Brandström ESPN 2015 Brussels 26

Nitrofurantoin Absorbed completely in proximal intestine Low impact on commensal flora Rapid renal elimination Urine concentrations depends on renal function Not recommended if GFR <40 ml/min/1,73 m 2 Higher risk of recurrence if dose is omitted Selection of resistant bacteria still unusual Adverse effects Nausea and vomiting Polyneuropathy at high plasma concentrations (low GFR) Pulmonary complications mainly in adults and elderly Formula unsuitable for children Tablets only, bad taste Recommended dose 1 mg/kg once daily Per Brandström ESPN 2015 Brussels 27

Amoxicillin/clavulanate Amoxicillin alone not recommended High rate of resistance in E. coli Resistance can emerge during treatment Much lower resistance to the combination amoxicillin/clavulanate Increased resistance after recent exposure Impact on individual level on the development of resistance Recommended dose 15 mg/kg once daily Per Brandström ESPN 2015 Brussels 28

Cefalosporins Cefaclor where nitrofurantoin is not available Little influence on intestinal microflora Different from other cefalosporins Other cefalosporins Strong impact on commensal flora Increasing rate of resistance Per Brandström ESPN 2015 Brussels 29

Obstacles to antibiotic prophylaxis Bacterial resistance Low adherence Decreases with patient age More evident for nitrofurantoin Recurrences with sensitive bacteria Efficacy questioned Per Brandström ESPN 2015 Brussels 30

Other prophylactic measures Reduce the use of antibiotics Breastfeeding More stable bacterial environment Male circumcision Infant period Posterior urethral valve Boys with dilated VUR or other malformation? If recurrent UTI only Surgical correction of dilating VUR and obstruction Enhanced emptying Clean Intermittent Catheterization Bladder or ureteral diversion Mårild et al, Pediatr Infect Dis J 1989;8: 511-15 Mårild et al, Acta Paediatr 2004;93:164-8 Bader and McCarthy, Pediatr Nephrol 2013;28:2267-72 Singh-Grewal et al, Arch Dis Child 2005;90:853 8 Per Brandström ESPN 2015 Brussels 31

Other prophylactic measures Treatment of bladder dysfunction and constipation Early toilet training Urotherapy Non-treatment of asymptomatic bacteriuria Protects from invasion of more virulent bacteria Often stable for years without symptoms If eradicated symptomatic recurrence common Inoculation of ABU-strain Hansson et al, Pediatrics 1989;84: 964-8 Sunden et al, J Urol 2010;184: 179-85 Cranberry juice Not recommended (Cochrane review 2012) Probiotics In one study effect equal to antibiotic prophylaxis Jepson et al, Cochrane Database Syst Rev 2012;10 Lee et al, Pediatr Nephrol 2007;22: 1315-20 Per Brandström ESPN 2015 Brussels 32

Key summary points No benefit from prophylaxis normal urinary tracts non-dilating VUR Strong correlation between UTI, dilating VUR and renal scarring Children at risk of recurrent UTI and acquired renal scarring seem to gain from antibiotic prophylaxis young children, mainly girls with dilating VUR Major obstacles to successful prophylaxis regimen increasing bacterial resistance low adherence Per Brandström ESPN 2015 Brussels 33

Prophylaxis or not Alternative measures to reduce UTI recurrences should be emphasized Prophylaxis can protect from recurrent UTI and long-term sequelae Selected patients Carefully followed Per Brandström ESPN 2015 Brussels 34

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