Urinary urologic procedures, however there is little such data

  Urinary tract infection (UTI) is one of the most commonbacterial infections in childhood affecting up to 2% of boys and 8% of girls by7 years of age.1 UTI is associated withrenal scarring and may lead to hypertension, proteinuria, and permanent renaldamage.2-5 Givena frequency of reinfection of up to 30%, it became common practice to prescribecontinuous low-dose antibiotic prophylaxis to prevent further UTIs in children,particular in those with risk factors for recurrent infections.6 More recently, thispractice has been questioned with attention to both the efficacy as well as thepotential harm of long-term antibiotics. This article reviews continuousantibiotic prophylaxis utilization in pediatric urology.  Abrief historyAs early as 1965, Normand et al. reported an associationbetween recurrent UTI in children and subsequent renal damage leading totreatment with continuous antibiotics, primarily sulphadimidine orsulphafurazole with nitrofurantoin or ampicillin less often.

7 Ultimately, continuous antibioticprophylaxis evolved to be primarily trimethoprim (2 mg/kg/day) and sulfamethoxazole(10 mg/kg/day) given twice daily or daily nitrofurantoin (2-4 mg/kg/day).7, 8 Efficacywas demonstrated with a decrease in asymptomatic bacteriuria found with regularscreening or with a decrease in the number of symptomatic UTIs during treatment.7, 9 Uropathogensensitivity to other available antimicrobial agents was deemed a successful prophylaxiscourse. Interestingly, a reduction in the number of rectal flora as well as theconcentration of resistant rectal bacteria, thought to be the cause ofrecurrent UTI, was also noted to be important.10 Active treatment toprevent recurrent UTIs ultimately became so common practice that a controlgroup without such measures had not been included in studies until the lastdecade.11  ANTIBIOTICSELECTIONOffice1  The AUABest Practice Policy Statement carefully reports recommended antimicrobialagents and doses for various urologic procedures, however there is little suchdata for continuous antibiotic prophylaxis.

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12 Cotrimoxazole,nitrofurantoin and trimethoprim are commonly used for this purpose. A 2010Cochrane Review of long-term antibiotics for preventing recurrent urinary tractinfections in children reports that nitrofurantoin was more effective thantrimethoprim or cotrimoxazole in preventing repeat symptomatic infection orrepeat positive urine culture. Though, it was associated with a greater numberof side effects (nausea, vomiting or stomach ache) suggesting thatnitrofurantoin may not be an acceptable therapy.13 INDICATIONS VesicoureteralRefluxOffice2 Vesicoureteral reflux has historically been managed with continuousantibiotic prophylaxis due to the concern for increased risk of repeatedpyelonephritis.14 More recently, thispractice has been questioned. There have been eight recent randomizedcontrolled trials comparing the impact of continuous antibiotic prophylaxis to acontrol group in children with vesicoureteral reflux.15-22However, experts remain conflicted as to how to summarize these data becausethese studies report somewhat conflicting results, perhaps dueto different inclusion criteria and study heterogeneity.

 Four of these trials demonstrated that use of continuous antibioticprophylaxis in the setting of reflux leads to an overall 37% reduction in UTI.23 Roussey-Kesslerenrolled 225 patients with Grade I-III reflux and concluded that there was nosupport for continuous antibiotic prophylaxis overall, however aslight decrease in recurrent infection was found in a subgroup of boys (alluncircumcised) with grade III vesicoureteral reflux, suggesting a differentrecommendation for this subgroup.22 The Swedish Reflux Trialin Children evaluated 200 children with Grades III and IV reflux and concludedthat continuous antibiotic prophylaxis decreases the febrile UTIrate in girls though did not note this decrease in boys, which may beattributable to the low baseline prevalence of UTI in boys older than 1 year ofage.15 The largest trials bothdemonstrated a modest benefit for continuous antibiotic prophylaxis.

The Prevention of Recurrent Urinary Tract Infection in Children with VesicouretericReflux and Normal Renal Tracts (PRIVENT) trial studied 576 children, 42% withvesicoureteral reflux, approximately half with at least Grade III, anddemonstrated an absolute risk reduction of UTI of 6% across all subgroups ofpatients.16 Most recently, theRandomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trialenrolled over 600 children with Grades I – IV reflux.19 Similar to the resultsof the PRIVENT trial, the RIVUR trial also demonstrated a modest benefit of continuousantibiotic prophylaxis across all subgroups.

 The four remaining studies did not demonstrate a reductionin the rate of UTI among children with reflux treated with continuous antibioticprophylaxis. Pennesi and colleagues included 100 children with gradesII-IV reflux and found no difference in the number of patients with recurrentfebrile UTI regardless of sex.21 Similarly, Montini etal. evaluated over 300 children with no or grade I–III VUR and found nodifference in the number of febrile recurrences.20 Garin et al.

studiedover 200 patients with low grade vesicoureteral reflux and concluded that therewas no support for continuous antibiotic prophylaxis in this group.17 Finally, Hari et al.enrolled children with grade I – IV reflux (73% with grade III – IV) and founda slight increased risk of developingsymptomatic UTI in those treated with continuous antibiotic prophylaxis.18 While each of these eight trials have different patientcohorts with quality limitations, often with inadequate blinding and/or varyingdefinitions of UTI, meta-analyses have been performed to address theconflicting results. Inclusive of the RIVUR trial, Wang et al. demonstratedthat continuous antibiotic prophylaxis significantly reduced the risk ofrecurrent febrile or symptomatic UTI (pooled OR 0.63) though there wassignificant study heterogeneity.

24 In practice, thedecision to use continuous antibiotic prophylaxis cannot be simplified to a summarystatistic and is multifactorial, based on factors that contribute to risk ofrecurrent UTI including age, sex Office3 and circumcision status, clinical presentation, reflux grade, andco-morbidities such as bladder and bowel dysfunctionOffice4 .23  Given these complexities, current guidelines shareinconsistencies. The American Urologic Association (AUA) recommendscontinuous antibiotic prophylaxis for children less than one year of age withreflux and a history of febrile UTI orwith higher grade reflux, defined as Grades III – V, identified throughscreening. In children greater than one year of age, continuousantibiotic prophylaxis is recommended in thesetting of bladder and bowel dysfunction given the increased incidence ofbreakthrough UTI in these children. However, for those without bladder andbowel dysfunction, recurrent febrile UTI, or renal cortical abnormalities,there is no consensus regarding superiority of either continuousantibiotic prophylaxis or observation.

25 The American Academy of Pediatrics subcommittee on UTIpublished guidelines for the diagnosis and evaluation of febrile UTI in childrenless than 24 months of age.26 In contrast to the AUA guidelines, these base theirrecommendations on a six-study meta-analysis (excluding the RIVUR trial andHari et al.) that did not demonstrate a benefit of continuousantibiotic prophylaxis in children with reflux. Therefore, these guidelinesdo not recommend a voiding cystourethrogram after a febrile UTI in the settingof a normal renal ultrasound; thus, reflux would not be diagnosed nor continuousantibiotic prophylaxis initiated. Controversy remains regarding the useof continuous antibiotic prophylaxis in children with reflux.More randomized, controlled trials will continue to refine the optimalmanagement of these patients.

 HydronephrosisPrenatal Office5 hydronephrosis is one of the most commonanomalies detected on prenatal ultrasonography, reported in 1–5% of allpregnancies.27 Postnatal treatment withcontinuous antibiotic prophylaxis had been recommended toreduce the rate of UTIs.28 However, there has beena paucity of high-level data evaluating the risk of UTI in those with nonrefluxingprenatal hydronephrosis. Braga and colleagues performed a meta-analysis todetermine the value of continuous antibiotic prophylaxisin reducing the rate of UTIs in this patient population.11 They included 21 observationalstudies of children with prenatal hydronephrosis and concluded that childrenwith high-grade prenatal hydronephrosis may benefit from continuousantibiotic prophylaxis with a reduced UTI rate (14.6% on prophylaxis versus 28.9% not on continuousantibiotic prophlaxis, p<0.01).

Incontrast, children with low-grade prenatal hydronephrosis were not shown tobenefit from continuous antibiotic prophylaxis (2.2%on prophylaxis versus 2.8% not on prophylaxis, p=0.51). However,the publications contributing to this review recognized shortcomings, includinglimited number of patients, event monitoring, and medication adherenceassessment. Additionally, due to the paucity of data, the impact of importantvariables known to contribute to UTI development such as sex and circumcisionstatus and vesicoureteral reflux grade could not be assessed.

5  More recently, Easterbrook et al. performed a repeatmeta-analysis including only studies directly comparing treatment with andwithout continuous antibiotic prophylaxis.29 11 observational studieswere included and there was not a significant difference in UTI rate among patientstreated with continuous antibiotic prophylaxis (9.

9%)and those not treated with continuous antibiotic prophylaxis (7.5%). However, only 5studies reported UTI rates based on hydronephrosis grade, which wasinsufficient to examine the association between grade and UTI rate stratifiedby treatment with continuous antibiotic prophylaxis. Similarly, stratificationby sex, circumcision status, and vesicoureteral reflux was not possible. The low-qualityevidence generated by these reviews underscores the importance of conductinghigh-quality research on continuous antibiotic prophylaxis for prenatalhydronephrosis patients, one such study which is currently underway.30 Whilemore data will further elucidate these nuances, current literature supports observationrather than continuous antibiotic prophylaxis in patients with low-gradehydronephrosis. PostoperativeOffice6 The AUABest Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxisstates that “surgical antimicrobialprophylaxis is recommended only when the potential benefit exceeds the risksand anticipated costs”.

12 Astudy by Hshieh et al. found that >90% of pediatric urologists treatpatients who have undergone a hypospadias repair with postoperative catheterwith postoperative antibiotics, though there islittle high-level data supporting this practice.31 Pediatric urologists widely use bothperioperative and postoperative antibiotics in hypospadias repair to not onlyreduce the risk of a post-operative UTI, but also to reduce the risk of meatalstenosis and fistula.32 However, several recent studies havequestioned this practice.

32-34 One such study performed by Zeiai et al. after uniformlychanging their standard antibiotoic practice from treating patients undergoinghypospadias repair with 14 days of prophylaxis post-operatively to 1 dosepreoperatively and evaluated the outcomes of 113 primary tubularized incisedplate repairs with postoperative stents. They found a lower complication ratein the group with lower antibiotic dose (29%) versus in the group withprophylaxis (16%) with equivalent infection rates (4% in lower dose versus 5%in prophylaxis group). These studies are not blinded, placebo-controlled, orrandomized and they have short follow-up periods. However, it draws attentionto the importance of recognizing that prolonged antibiotic use that has beenpracticed historically is now being interrogated. RESISTANCE Antibiotic resistance is a global public health problem asacknowledged by the World Health Organization, which reports “antibioticresistance is one of the biggest threats to global health, food security, anddevelopment today”.35 Antibiotic resistant infections are twice aslikely to be associated with greater morbidity and mortality and are alsoassociated with increased healthcare costs.

36 Specific to UTI, the resistance pattern ofuropathogens has been evolving. Compared with the years 2002–2004, in 2009trimethoprim/sulfamethoxazole resistance rates for E. coli pediatric UTIsincreased in both boys (from 23% up to 31%) and girls (from 20% up to 23%). Therewas also a 10-fold increase in E. coli resistance to ciprofloxacin inboys (from 1% in 2002–2004 to 10% in 2009) and girls (from 0.6% to 4%) inpediatric UTIs.

5, 37, 38  Even briefantibiotic use has lasting effects. Studies performed in adults treated for UTIwith antibiotics have found bacterial isolates in the urinary tract have morethan 13 times the odds of antibiotic resistance with resistance detected up to12 months.39, 40 Regarding continuousantibiotic prophylaxis, Conwayand colleagues reviewed over 600 children with first UTI and 83 with recurrentUTI and found that continuous antibiotic prophylaxis was a risk factor for antimicrobialresistance (HR 7.50). 41 In fact, this resistance extends beyondthe prophylactic agent. Cheng et al.

reports that those who receivedcephalosporin prophylaxis are more likely to have extended-spectrum ?-lactamase-producing bacteria or multidrug resistanturopathogens.42  AdherenceFurther complicating anunderstand of the impact of continuous antibiotic prophylaxis is evidence that (1)adherence to continuous antibiotic prophylaxis is poor and (2) poor adherencemay lead to an increased risk for antibiotic resistance.5 In fact, adherence rates among patients with chronicconditions drops dramatically after the first six months of therapy and pooradherence accounts for substantial worsening of disease and increased healthcare costs in the United States.43 Concern with adherence to continuousantibiotic prophylaxis has been reported since its initiation. Daschner andMargeret (1975) report only 71% of patients took their prescribed treatment atall with only 32% taking it as prescribed.44 Unfortunately, measuring accurate adherencerates remains challenging without any method considered a gold standard. In thestudy performed by Montini et al. comparing treatment with continuous antibioticprophylaxis versus no treatment, two methods were utilized and differentresults were obtained.

Antimicrobial activity was tested in approximatelyone-third of urine cultures from patients treated with continuousantibiotic prophylaxis and found 71% tested positive while 86% ofpatients reported “good compliance” on the visual analog scale questionnaire.20 In fact, direct approaches to measures adherence, such as urinetesting, are expensive and do not measure long-term adherence while indirect measures,frequently utilizing caregiver questionnaires, are susceptive to misrepresentationand often lead to overestimation of adherence.43 Even electronic measures are challenging in thispopulation as traditional Medication Electronic Monitoring System technology isnot suitable for use with liquid medication.45 Studies directlyevaluating adherence find that adherence to long-term therapies is often poor. Usinga large pharmacy claims database, Copp et al. determined that 60% of childrenwith reflux were not adherent with continuous antibiotic prophylaxis.46 Similarly, other studies evaluating adherenceamong children prescribed continuous antibioticprophylaxis have consistentlydemonstrated adherence rates <30%, which is significantly lower thanadherence rates published in many trials evaluating response to continuousantibiotic prophylaxis.

47-49 Nonadherence not only confounds the results of studiesevaluating the impact of continuous antibiotic prophylaxis, but may also hasten the development ofantibiotic resistance.50, 51  CONCLUSIONS Whilecontinuous antibiotic prophylaxis was first used as a treatment strategy for theprevention of recurrent UTI in the 1960s, many studies are now interrogating itsclinical efficacy. Additionally, it is important that these benefits are balancedwith an understanding of the impact of antibiotic use on the development of antibioticresistance, which is now a global problem.

It is clear that some children will havea reduced rate of recurrent UTI when treated with continuous antibiotic prophylaxis.However, it remains unclear exactly which subset of those at risk will benefit.Given this uncertainty, current guidelines allow physicians to provide individualizedcare. As more high-quality studies are conducted, we anticipate a better understandingnot only regarding who will benefit from continuous antibiotic prophylaxis, but also how to minimize thepropagation of antibiotic resistance and how to improve adherence to thesetreatment regimens.