Urinary tract infection (UTI) is one of the most common
bacterial infections in childhood affecting up to 2% of boys and 8% of girls by
7 years of age.1 UTI is associated with
renal scarring and may lead to hypertension, proteinuria, and permanent renal
damage.2-5 Given
a frequency of reinfection of up to 30%, it became common practice to prescribe
continuous low-dose antibiotic prophylaxis to prevent further UTIs in children,
particular in those with risk factors for recurrent infections.6 More recently, this
practice has been questioned with attention to both the efficacy as well as the
potential harm of long-term antibiotics. This article reviews continuous
antibiotic prophylaxis utilization in pediatric urology.

 

A
brief history

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As early as 1965, Normand et al. reported an association
between recurrent UTI in children and subsequent renal damage leading to
treatment with continuous antibiotics, primarily sulphadimidine or
sulphafurazole with nitrofurantoin or ampicillin less often.7 Ultimately, continuous antibiotic
prophylaxis 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 Efficacy
was demonstrated with a decrease in asymptomatic bacteriuria found with regular
screening or with a decrease in the number of symptomatic UTIs during treatment.7, 9 Uropathogen
sensitivity to other available antimicrobial agents was deemed a successful prophylaxis
course. Interestingly, a reduction in the number of rectal flora as well as the
concentration of resistant rectal bacteria, thought to be the cause of
recurrent UTI, was also noted to be important.10 Active treatment to
prevent recurrent UTIs ultimately became so common practice that a control
group without such measures had not been included in studies until the last
decade.11

 

ANTIBIOTIC
SELECTIONOffice1 

 

The AUA
Best Practice Policy Statement carefully reports recommended antimicrobial
agents and doses for various urologic procedures, however there is little such
data for continuous antibiotic prophylaxis.12 Cotrimoxazole,
nitrofurantoin and trimethoprim are commonly used for this purpose. A 2010
Cochrane Review of long-term antibiotics for preventing recurrent urinary tract
infections in children reports that nitrofurantoin was more effective than
trimethoprim or cotrimoxazole in preventing repeat symptomatic infection or
repeat positive urine culture. Though, it was associated with a greater number
of side effects (nausea, vomiting or stomach ache) suggesting that
nitrofurantoin may not be an acceptable therapy.13

 

INDICATIONS

 

Vesicoureteral
RefluxOffice2 

Vesicoureteral reflux has historically been managed with continuous
antibiotic prophylaxis due to the concern for increased risk of repeated
pyelonephritis.14 More recently, this
practice has been questioned. There have been eight recent randomized
controlled trials comparing the impact of continuous antibiotic prophylaxis to a
control group in children with vesicoureteral reflux.15-22
However, experts remain conflicted as to how to summarize these data because
these studies report somewhat conflicting results, perhaps due
to different inclusion criteria and study heterogeneity.

 

Four of these trials demonstrated that use of continuous antibiotic
prophylaxis in the setting of reflux leads to an overall 37% reduction in UTI.23 Roussey-Kessler
enrolled 225 patients with Grade I-III reflux and concluded that there was no
support for continuous antibiotic prophylaxis overall, however a
slight decrease in recurrent infection was found in a subgroup of boys (all
uncircumcised) with grade III vesicoureteral reflux, suggesting a different
recommendation for this subgroup.22 The Swedish Reflux Trial
in Children evaluated 200 children with Grades III and IV reflux and concluded
that continuous antibiotic prophylaxis decreases the febrile UTI
rate in girls though did not note this decrease in boys, which may be
attributable to the low baseline prevalence of UTI in boys older than 1 year of
age.15 The largest trials both
demonstrated a modest benefit for continuous antibiotic prophylaxis.
The Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric
Reflux and Normal Renal Tracts (PRIVENT) trial studied 576 children, 42% with
vesicoureteral reflux, approximately half with at least Grade III, and
demonstrated an absolute risk reduction of UTI of 6% across all subgroups of
patients.16 Most recently, the
Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial
enrolled over 600 children with Grades I – IV reflux.19 Similar to the results
of the PRIVENT trial, the RIVUR trial also demonstrated a modest benefit of continuous
antibiotic prophylaxis across all subgroups.

 

The four remaining studies did not demonstrate a reduction
in the rate of UTI among children with reflux treated with continuous antibiotic
prophylaxis. Pennesi and colleagues included 100 children with grades
II-IV reflux and found no difference in the number of patients with recurrent
febrile UTI regardless of sex.21 Similarly, Montini et
al. evaluated over 300 children with no or grade I–III VUR and found no
difference in the number of febrile recurrences.20 Garin et al. studied
over 200 patients with low grade vesicoureteral reflux and concluded that there
was 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 found
a slight increased risk of developing
symptomatic UTI in those treated with continuous antibiotic prophylaxis.18

 

While each of these eight trials have different patient
cohorts with quality limitations, often with inadequate blinding and/or varying
definitions of UTI, meta-analyses have been performed to address the
conflicting results. Inclusive of the RIVUR trial, Wang et al. demonstrated
that continuous antibiotic prophylaxis significantly reduced the risk of
recurrent febrile or symptomatic UTI (pooled OR 0.63) though there was
significant study heterogeneity.24 In practice, the
decision to use continuous antibiotic prophylaxis cannot be simplified to a summary
statistic and is multifactorial, based on factors that contribute to risk of
recurrent UTI including age, sex Office3 and circumcision status, clinical presentation, reflux grade, and
co-morbidities such as bladder and bowel dysfunctionOffice4 .23

 

Given these complexities, current guidelines share
inconsistencies. The American Urologic Association (AUA) recommends
continuous antibiotic prophylaxis for children less than one year of age with
reflux and a history of febrile UTI or
with higher grade reflux, defined as Grades III – V, identified through
screening. In children greater than one year of age, continuous
antibiotic prophylaxis is recommended in the
setting of bladder and bowel dysfunction given the increased incidence of
breakthrough UTI in these children. However, for those without bladder and
bowel dysfunction, recurrent febrile UTI, or renal cortical abnormalities,
there is no consensus regarding superiority of either continuous
antibiotic prophylaxis or observation.25 The American Academy of Pediatrics subcommittee on UTI
published guidelines for the diagnosis and evaluation of febrile UTI in children
less than 24 months of age.26 In contrast to the AUA guidelines, these base their
recommendations on a six-study meta-analysis (excluding the RIVUR trial and
Hari et al.) that did not demonstrate a benefit of continuous
antibiotic prophylaxis in children with reflux. Therefore, these guidelines
do not recommend a voiding cystourethrogram after a febrile UTI in the setting
of a normal renal ultrasound; thus, reflux would not be diagnosed nor continuous
antibiotic prophylaxis initiated. Controversy remains regarding the use
of continuous antibiotic prophylaxis in children with reflux.
More randomized, controlled trials will continue to refine the optimal
management of these patients.

 

Hydronephrosis

Prenatal Office5 hydronephrosis is one of the most common
anomalies detected on prenatal ultrasonography, reported in 1–5% of all
pregnancies.27 Postnatal treatment with
continuous antibiotic prophylaxis had been recommended to
reduce the rate of UTIs.28 However, there has been
a paucity of high-level data evaluating the risk of UTI in those with nonrefluxing
prenatal hydronephrosis. Braga and colleagues performed a meta-analysis to
determine the value of continuous antibiotic prophylaxis
in reducing the rate of UTIs in this patient population.11 They included 21 observational
studies of children with prenatal hydronephrosis and concluded that children
with high-grade prenatal hydronephrosis may benefit from continuous
antibiotic prophylaxis with a reduced UTI rate (14.6% on prophylaxis versus 28.9% not on continuous
antibiotic prophlaxis, p90% of pediatric urologists treat
patients who have undergone a hypospadias repair with postoperative catheter
with postoperative antibiotics, though there is
little high-level data supporting this practice.31 Pediatric urologists widely use both
perioperative and postoperative antibiotics in hypospadias repair to not only
reduce the risk of a post-operative UTI, but also to reduce the risk of meatal
stenosis and fistula.32 However, several recent studies have
questioned this practice.32-34 One such study performed by Zeiai et al. after uniformly
changing their standard antibiotoic practice from treating patients undergoing
hypospadias repair with 14 days of prophylaxis post-operatively to 1 dose
preoperatively and evaluated the outcomes of 113 primary tubularized incised
plate repairs with postoperative stents. They found a lower complication rate
in the group with lower antibiotic dose (29%) versus in the group with
prophylaxis (16%) with equivalent infection rates (4% in lower dose versus 5%
in prophylaxis group). These studies are not blinded, placebo-controlled, or
randomized and they have short follow-up periods. However, it draws attention
to the importance of recognizing that prolonged antibiotic use that has been
practiced historically is now being interrogated.

 

RESISTANCE

 

Antibiotic resistance is a global public health problem as
acknowledged by the World Health Organization, which reports “antibiotic
resistance is one of the biggest threats to global health, food security, and
development today”.35 Antibiotic resistant infections are twice as
likely to be associated with greater morbidity and mortality and are also
associated with increased healthcare costs.36 Specific to UTI, the resistance pattern of
uropathogens has been evolving. Compared with the years 2002–2004, in 2009
trimethoprim/sulfamethoxazole resistance rates for E. coli pediatric UTIs
increased in both boys (from 23% up to 31%) and girls (from 20% up to 23%). There
was also a 10-fold increase in E. coli resistance to ciprofloxacin in
boys (from 1% in 2002–2004 to 10% in 2009) and girls (from 0.6% to 4%) in
pediatric UTIs.5, 37, 38

 

Even brief
antibiotic use has lasting effects. Studies performed in adults treated for UTI
with antibiotics have found bacterial isolates in the urinary tract have more
than 13 times the odds of antibiotic resistance with resistance detected up to
12 months.39, 40 Regarding continuous
antibiotic prophylaxis, Conway
and colleagues reviewed over 600 children with first UTI and 83 with recurrent
UTI and found that continuous antibiotic prophylaxis was a risk factor for antimicrobial
resistance (HR 7.50). 41 In fact, this resistance extends beyond
the prophylactic agent. Cheng et al. reports that those who received
cephalosporin prophylaxis are more likely to have extended-spectrum ?-lactamase-producing bacteria or multidrug resistant
uropathogens.42

 

Adherence

Further complicating an
understand of the impact of continuous antibiotic prophylaxis is evidence that (1)
adherence to continuous antibiotic prophylaxis is poor and (2) poor adherence
may lead to an increased risk for antibiotic resistance.5 In fact, adherence rates among patients with chronic
conditions drops dramatically after the first six months of therapy and poor
adherence accounts for substantial worsening of disease and increased health
care costs in the United States.43 Concern with adherence to continuous
antibiotic prophylaxis has been reported since its initiation. Daschner and
Margeret (1975) report only 71% of patients took their prescribed treatment at
all with only 32% taking it as prescribed.44 Unfortunately, measuring accurate adherence
rates remains challenging without any method considered a gold standard. In the
study performed by Montini et al. comparing treatment with continuous antibiotic
prophylaxis versus no treatment, two methods were utilized and different
results were obtained. Antimicrobial activity was tested in approximately
one-third of urine cultures from patients treated with continuous
antibiotic prophylaxis and found 71% tested positive while 86% of
patients reported “good compliance” on the visual analog scale questionnaire.20 In fact, direct approaches to measures adherence, such as urine
testing, are expensive and do not measure long-term adherence while indirect measures,
frequently utilizing caregiver questionnaires, are susceptive to misrepresentation
and often lead to overestimation of adherence.43 Even electronic measures are challenging in this
population as traditional Medication Electronic Monitoring System technology is
not suitable for use with liquid medication.45

 

Studies directly
evaluating adherence find that adherence to long-term therapies is often poor. Using
a large pharmacy claims database, Copp et al. determined that 60% of children
with reflux were not adherent with continuous antibiotic prophylaxis.46 Similarly, other studies evaluating adherence
among children prescribed continuous antibiotic
prophylaxis have consistently
demonstrated adherence rates