Routine Use of Antibiotic Prophylaxis in Paediatric Vesico-ureteric reflux (VUR) Dr Kalli Spencer Wits University

FOR the use of Antibiotics

Rationale Daily prophylactic administration of an antibiotic agent. Use of continuous antibiotics results in sterile urine Continued reflux of sterile urine does not cause renal damage Antimicrobial agents most commonly used for prophylaxis include  Trimethoprim-sulfamethoxazole (TMP-SMZ)  Trimethoprim alone  Nitrofurantoin Once daily dose at bedtime The dose is one-half to one-quarter the usual therapeutic dose.

Brandstrom P, Esbjorner E, Herthelius M, et al. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010; 184:286. High-quality clinical trial Result: prophylactic antibiotic reduces the risk of recurrent UTI in young children with VUR. Decrease in UTI and renal scarring in children with grades III or IV reflux who were either on prophylaxis or treated endoscopically, when compared with those who were observed.

Sillén U, Brandström P, Jodal U, et al. The Swedish refl ux trial in children: v. Bladder dysfunction. J Urol 2010; 184: 298–304. Brandström P, Esbjörner E, Herthelius M, et al. The Swedish reflux trial in children: I. Study design and study population characteristics. J Urol 2010; 184: 274– children aged between 1 and 2 years who had grade III or IV vesicoureteric reflux were randomised to one of three groups: 1)Low-dose prophylactic antibiotics (n=69); Trimethoprim (0.5-1mg/kg dly), Nitrofurantoin 1mg/kg dly, cefadroxil 5mg/kg dly 2) Endoscopic treatment with dextranomer and hyaluronic acid (n=66); 3) Surveillance with early antibiotic treatment if a urinary tract infection occurred (n=68).

Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish refl ux trial in children: III. Urinary tract infection pattern. J Urol 2010; 184: 286–91. The results were initially better in the group that received dextranomer and hyaluronic acid, but 20% of those children had recurrent dilating vesicoureteric reflux after 2 years.

Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish refl ux trial in children: IV. Renal damage. J Urol 2010; 184: 292–97. Recurrent febrile urinary tract infections occurred in 42 (33%) of 128 girls and in seven (9%) of 75 boys studied. The proportions of recurrent infections differed significantly between the treatment and surveillance groups: 19% of girls receiving cotrimoxazole prophylaxis 23% receiving dextranomer and hyaluronic acid 57% of those surveyed (p=0∙0002)

Holmdahl G, Brandström P, Läckgren G, et al. The Swedish refl ux trial in children: II. Vesicoureteric reflux outcome. J Urol 2010; 184: 280–85. New renal scars developed in: 6% of children treated with cotrimoxazole, 12% treated with dextranomer and hyaluronic acid 18% undergoing surveillance. The difference was significant for prophylaxis versus surveillance (p<0∙0005) but not for other comparisons.

RIVUR Trial Investigators, Hoberman A, Greenfield SP, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014; 370:2367. Carpenter MA, Hoberman A, Mattoo TK, et al, and the RIVUR Trial Investigators. The RIVUR trial: profile and baseline clinical associations of children with vesicoureteric refl ux. Pediatrics 2013; 132: e34–45. The Randomized Intervention for Vesicoureteral Reflux trial reported that prophylactic antibiotics reduced the risk of recurrent infection compared with placebo. In this more rigorous multicenter trial, the effectiveness of trimethoprim-sulfamethoxazole (TMP-SMX) and placebo were compared in 607 children (two months to six years) with VUR over a two-year follow-up period. TMP-SMX dose 3mg/kg dly Patients were initially diagnosed with grade I to IV VUR after a first or second febrile or symptomatic UTI.

The following findings were noted: Overall, children in the TMP-SMX group were less likely to have recurrent febrile or symptomatic UTI than those in the placebo group (13 versus 24 percent) (hazard ratio [HR] 0.50, 95% CI ). In subgroup analysis, antibiotic prophylaxis was most effective in children with bowel and bladder dysfunction (HR 0.21, 95% CI ) and in children whose first UTI was febrile (HR 0.41, 95% CI ). The time to first UTI: days in placebo group days in the prophylaxis group. In addition, the number of children deemed “treatment failures” who then went off study medication on to other interventions was double in the placebo group (9.6 versus 5 percent).

Children with grade III or IV VUR were more likely to have febrile or symptomatic UTI than those with grade I or II VUR (23 versus 14 percent). In subgroup analysis, TMP-SMX prophylaxis was associated with a lower risk of recurrent febrile or symptomatic UTI in patients with grade I or II VUR (HR 0.32, 95% CI ). Antibiotic prophylaxis appeared to be associated with a lower risk of recurrent febrile or symptomatic UTI in patients with grade III or IV VUR, (HR 0.66, 95% CI ).

TMP-SMX prophylaxis compared with placebo did not reduce Incidence of renal scarring (11 and 10.2 percent) Severe renal scars (4 and 2.5 percent) New renal scars (8.2 and 8.4 percent) as assessed by renal scintigraphy at two-year follow-up. No significant increase in resistant E. coli in stool was noted (28 versus 20 percent).

No short-term benefit has been demonstrated for preventing renal scarring. In the RIVUR trial, there was an overall lower risk of renal scarring than had been reported in previously published retrospective data. Other studies showed underreporting This may be due to the close monitoring of patients including early diagnosis and prompt treatment of UTI, and a relatively short duration of follow-up of two years.

Craig, JC. Antibiotics prophylaxis and Recurrent Urinary Tract Infection in children. N Engl J Med 2009; 361: [Privent] children randomised (median age 14mo. 64% girls.) -42 % had VUR (53% had Grade III) -TMP 2mg/kg/d and SMX 10mg/kg/d -UTI developed in  13% of patients receiving Cotrimoxazole  19% of placebo patients - In the antibiotic group: The reduction of urinary tract infection appeared to be consistent across all subgroups

Williams G, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2011; 3: CD Benefit of low dose antibiotics to prevent repeat symptomatic UTI in children.

Williams G, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2011; 3: CD Data show little adverse events from antibiotic treatment

REBUTTAL

Shortcomings of the studies Small patient numbers High dropout rates Inaccurate urine collection methods ( i.e. bags) No placebo controls Routine screening rather than evaluation in response to symptoms including screened bagged sample collections in uncircumcised infants Lack of distinction between febrile and afebrile UTIs Single UTI Low grades of VUR Very little renal damage (when assessed) Short follow up

Urine Sample Collection Method

Bladder Bowel Dysfunction

40% of children with “primary reflux” have an associated dysfunctional elimination syndrome. [secondary reflux] Koff, SA. Lapides, J. piezza DH. Associations of urinary tract infection and reflux with uninhibited bladder contraction and voluntary sphincter dysfunction. Jurol 1979; 122:373 Dysfunctional elimation syndrome43% Bladder overactivity27% Lazy Bladder23% Constipation50%

Follow up Data on long-term outcome (ie, greater than two years) are needed to evaluate the role of any intervention in the prevention of renal scarring and chronic kidney disease.

Odds Ratio Favouring CAP

Nagler EV, Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2011; :CD Did not detect an overall benefit for prophylaxis compared with no treatment in preventing recurrent UTI. However even the metanalysis is flawed because: There was considerable heterogeneity among the studies regarding: the age of the patients how the diagnosis of VUR was made In addition, this analysis was limited by the poor quality of the studies, as only one of the studies was blinded. Poor level of evidence even in large review shows that the quality of the data is poor.

Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011; 128:595. Another 2011 review of the literature limited to children between 2 and 24 months of age also did not find any benefit for antibiotic prophylaxis. Once again there were similar issues regarding the quality of the included studies. Subanalysis based on the severity of reflux also showed no difference between the two approaches, but analysis for each grade of reflux was limited by the small number of patients in each category (underpowered). As an example, in patients with grade IV VUR, the risk of recurrent infection for patients treated medically was lower compared with surveillance alone (29 versus 43 percent), but did not reach statistical significance (relative risk 0.73, 95% CI ).

Hari P Et al. Antibiotic prophylaxis in the management of vesicoureteric reflux: a randomized double-blind placebo-controlled trial. Pediatr Nephrol (2015) 30:479–486 In a double-blind study in India, 93 children with grade I–IV vesicoureteric reflux were randomised to receive either co- trimoxazole or placebo for 12 months. Of note was the finding that the children receiving prophylaxis developed significantly more recurrent infections than those receiving placebo (21% vs 6%, p=0∙02). Study number very low (93 patients)

Wang HH, Gbadegesin RA, Foreman JW, et al. Efficacy of antibiotic prophylaxis in children with vesicoureteral reflux: systematic review and meta-analysis. J Urol 2015; 193:963. A systematic review that included the RIVUR study also reported similar results that prophylactic antibiotics reduced the risk of febrile and symptomatic UTI in children with VUR. However, there was a higher risk of a UTI due to antibiotic-resistant bacteria, and there appeared to be no effect on the risk of developing renal scars. Of note, there was great heterogeneity among the studies including study design and quality

Williams G, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2011; 3: CD A meta-analysis showed that the risk for antibiotic resistance was reduced for children who had received nitrofurantoin compared with those who had received co-trimoxazole.

Lewis DA et al. Antimicrobial susceptibility of organisms causing community- acquired urinary tract infections in Gauteng Province, South Africa June 2013, Vol. 103, No. 6 SAMJ In the community Trimethoprim/ sulphamethoxazole was 44.3% susceptible; 95% CI ) compared to Nitrofurantoin (91.7%; 95% CI ) Cendron, M. Antibiotic prophylaxis in the Management of Vesicoureteral reflux. Advances in Urology. Vol 2008, Article ID Nitrofurantoin does not achieve significant levels in intestinal or vaginal tissues and does not alter the normal flora in these areas. Nitrofurantoin may minimise the development of resistance to fecal organisms, the latter being the largest reservoir for urine infectivity.

Karpman E, Kurzrock EA: Adverse reactions of nitrofurantoin, trimethoprim and sulfamethoxazole in children. J Urol. 172: Study by Karpman and Kurzrock (2004) revealed a low incidence of significant hepatic (5 patients) or pulmonary (9 patients) involvement, almost always associated with full-dose rather than a once-daily dosing. Less common than seen in adults because of the lower dose used for therapy, and the lack of significant comorbidities and drug interactions in children. Serious side effects are extremely rare and most are reversible by discontinuing therapy

Adverse effects of Long Term Nitrofurantoin

But we use Bactrim for HIV + children……. WHO Guidelines for Co-Trimoxazole recommendations for infants /children HIV exposed infants and children - TSX start at 4-6 weeks until RVD diagnosis made Confirmed HIV Positive - <1 yrs: TSX given regardless of CD4 percentage/clinical status yrs: Any WHO stage and CD4 <25% Universal option: TSX prophylaxis given to all infants and children born to mothers confirmed to be or suspected of living with HIV

Baquerizo B.A. Peters A.C. Antibiotic prophylaxis and reflux: critical review and assessment. F1000Prime Reports 2014, 6:104 Inappropriate to say that NO patients should be treated with prophylactic antibiotics. Clear indicators for using CAP are Multiple prior UTIs Renal scarring Dilating reflux (grades III to V) Abnormal voiding BBD Social factors such as parental preferences and attitudes.

Final Words…. Few studies performed in developing countries/emerging economies [BRIC countries] Underpowered studies (significant heterogeneity) providing poor evidence against antibiotic use ? Safe to apply to a paediatric population Consider if this was your own child……