<title>1. INTRODUCTION</title> <p>Vesicoureteral reflux (VUR) is defined as the
abnormal, retrograde flow of urine from the urinary bladder into the upper urinary
tract. VUR can be primary, caused by an anatomically insufficient
vesicoureteric junction, or secondary, due to an infravesical obstruction. VUR
affects 1–3% of otherwise
healthy children. However, the prevalence rises to 10–20% in children
with antenatally detected hydronephrosis, to 30% in siblings of children with
known VUR, and to 30–40% in children
with a proved urinary tract infection (UTI) [##REF##11009294##1##, ##REF##17558268##2##].</p> <p>The retrograde flow of urine from the bladder
into the ureter may transport bacteria to the upper urinary tract, possibly
predisposing these children to febrile UTI, which can result in permanent renal
parenchymal damage. Ultimately, renal damage results in reflux nephropathy which
could cause hypertension and decreased renal function although the risk seems
to be lower than previously thought [##REF##10768669##3##–##REF##16773411##5##].</p> <p>The clinical presentation of patients with VUR
is diverse and dependent on age and gender [##UREF##0##6##]. Typically, VUR is detected
during the evaluation of a child, usually a girl, presenting with UTI [##REF##12478178##7##].
Since the widespread use of prenatal ultrasonography, hydronephrosis is often
detected in utero, possibly
leading to the diagnosis of VUR in the perinatal period [##REF##14586679##8##]. Neonatal VUR is
more common in boys and often associated with congenital renal dysplasia. A
history of familial VUR and investigation of an overactive bladder can also lead
to the diagnosis of VUR [##REF##12394743##9##, ##REF##9719268##10##].</p> <p>In 1999, the practice guideline from the American Academy of Pediatrics recommended a
renal ultrasound and either a classic radiographic voiding cystourethrography
or a direct radionuclide cystography after a first UTI in children aged 2–24 months [##REF##10103321##11##].
However, the recently revised guideline of the National Institute for Health
and Clinical Excellence (NICE) constitutes a major departure from this
diagnostic strategy [##UREF##1##12##, ##REF##17717369##13##]. For infants and children without recurrent or atypical
UTI, no imaging tests are recommended when they are 6 months or older, and an
ultrasound within 6 weeks of the first UTI will suffice when they are younger
than 6 months.</p> <p>Spontaneous resolution of VUR due to the natural
elongation of the vesicoureteral junction is possible, especially in patients
with the lower grades of VUR or unilateral reflux and in
boys; grades I–III reflux
resolves at a rate of 13% each year during the first 5 years of follow-up and at
3.5% yearly thereafter, and grade IV reflux resolves at a yearly rate of 5% [##REF##12441993##14##].</p> <p>The main goal of the management of VUR should
be prevention of recurrent febrile UTI, and thereby prevention of the ensuing renal
parenchymal damage [##UREF##0##6##]. The treatment options include intermittent therapy of
episodes of UTI, medical therapy with long-term antibiotic prophylaxis, endoscopic
therapy, or surgical therapy.</p> <p>The desire to update our therapeutic algorithm
for children with VUR stimulated us to conduct a systematic review of the role
of antibiotic prophylaxis in the management of these children. More
specifically, we wanted to ascertain whether antibiotics can be safely
discontinued and whether prophylaxis is effective in the prevention of recurrent
UTIs and renal damage in these patients.</p>
<title>2. METHODS</title> <p>Medline (1966 to June 2008), Embase (1988 to
June 2008), and Cochrane Central Register of Controlled Trials were searched
using the combined search terms “vesicoureteral reflux” (MeSH) and “antibiotic
prophylaxis” (MeSH). National Guideline Clearinghouse, NICE Guidance, and
Cochrane Database of Systematic Reviews were searched using the search terms “vesicoureteral
reflux” and “urinary tract infection in children.” Reference lists of articles,
reviews, and studies were searched for additional studies.</p> <p>After the search was performed, the titles of
all retrieved publications were screened. If the title indicating the paper was
potentially relevant, the abstract was reviewed. The full paper was reviewed if
the abstract suggested that the paper was indeed relevant. This process was
performed by one reviewer (MC Michiel Costers)
and thereafter validated by two other reviewers (GB Guy Bogaert and RVDL Rita Van Damme-Lombaerts).</p> <p>Five uncontrolled studies evaluated the effect
of stopping antibiotic prophylaxis in this patient group [##REF##10604374##15##–##REF##16308218##19##].</p> <p>Five randomized controlled trials (RCTs) and
one cohort study that compared antibiotic prophylaxis with no treatment (i.e.,
surveillance with intermittent therapy of episodes of UTI) for children with
VUR were included in this review [##UREF##2##20##–##REF##18490378##25##].</p> <p>Two Cochrane systematic reviews and two
guidelines on the topic of antibiotic prophylaxis for children with VUR were
identified [##UREF##1##12##, ##UREF##4##26##–##REF##9112544##28##]. Instead of performing a meta-analysis on this limited
number of RCTs, we present the results of these studies.</p>
<title>3. RESULTS AND DISCUSSION</title> <p>Long-term antibiotic prophylaxis remains a
common practice in the management of children with VUR. The most commonly used
drugs are nitrofurantoin, cotrimoxazole, amoxicillin, and cephalosporins [##REF##11391331##29##, ##REF##16510674##30##].
However, these medications may cause side effects and promote the development
of resistant bacteria [##REF##16510640##22##, ##REF##17622599##23##, ##REF##18490378##25##, ##REF##16203936##31##]. Furthermore, the optimal duration of
prophylaxis and optimal (low) dose of antibiotic are unclear, and compliance with
this long-term treatment is not always assured.</p> <p>In the 1960's, animal data showed that a UTI in
the presence of VUR can cause renal damage. It was then hypothesized that
sterilization of the urine could prevent pyelonephritis, and thereby also the
resulting parenchymal damage.</p> <p>At the end of the 1970's, two very small
studies indeed suggested that prophylactic antibiotics may prevent recurrent
UTIs in children, particularly during the period of prophylaxis. Smellie et al.
[##UREF##6##32##] compared 6–12 months of
antibiotic prophylaxis (cotrimoxazole or nitrofurantoin) versus no treatment in
53 children with acute UTI. None of the children in the intervention group had
a UTI during the prophylaxis period, while 11 children in the control group
presented with a UTI. Twelve months after stopping prophylactic antibiotics, 8
children (32%) in the intervention group compared with 13 (64%) in the control
group had suffered from a recurrent UTI.</p> <p>Lohr et al. [##REF##322082##33##] performed a crossover study on
18 girls with a history of at least 3 episodes of bacteriuria in the previous
year (including 1 girl with VUR). Each child was placed on nitrofurantoin for 6
months and on placebo for a similar period. There were 35 episodes of
bacteriuria (4.2 episodes/patient/year) in
the patients taking the placebo versus 2 episodes (0.2 episodes/patient/year) in the children
taking the antibiotic. Fourteen symptomatic UTIs (1.7 episodes/patient/year) occurred during the
placebo periods, and none during the prophylaxis periods.</p> <p>In 1997, the Pediatric Vesicoureteral Reflux
Guidelines Panel of the American Urological Association (AUA) recommended
continuous antibiotic prophylaxis as initial therapy for children with reflux
grades I–IV [##REF##9112544##28##]. However,
this recommendation was based on expert opinion rather than on clear scientific
evidence.</p> <title>3.1. Discontinuation of antibiotic prophylaxis</title> <p>During the following decades, this therapeutic
practice has been challenged on multiple occasions. First, several authors
demonstrated that in certain circumstances antibiotic prophylaxis can be safely
discontinued.</p> <p>Cooper et al. [##REF##10604374##15##] discontinued antibiotic
prophylaxis in 51 children with persistent primary VUR (grades I–IV). All children
were old enough to describe the symptoms of UTI (mean age at stop of
antibiotics = 8.6 years), and had a minimal or questionable history of true UTI,
normal voiding patterns, and kidneys with no significant hydronephrosis or
scars. A retrospective chart review revealed 6 episodes (11.8%) of UTI after
cessation of prophylaxis (mean follow-up off antibiotics = 3.7 years): 1 case
of cystitis and 5 cases of clinically presumptive pyelonephritis. None of the
children showed new renal scars on renal ultrasound. However, it should be
noted that renal ultrasound has low sensitivity for detection of renal scars.</p> <p>The retrospective chart review by Thompson et
al. [##REF##11547114##16##] of 196 children (mean age at stop of antibiotics = 6 years) who had
been withdrawn from prophylactic antibiotics (mean follow-up off antibiotics =
3.4 years) despite persistent reflux (all grades) showed a similar rate of UTIs
per patient/year on
or off antibiotics (0.29 on versus 0.24 off). Paradoxically, for the 39
children with high-grade reflux IV or V, there was a difference in the rate of
UTIs per patient/year
seemingly in favor of discontinuation of antibiotic prophylaxis (0.39 on versus
0.18 off). In addition, the rate of new
renal scarring on DMSA scan after stop of antibiotics was comparable with the
rate during prophylaxis (2.6% on versus 3.6% off).</p> <p>Hellerstein and Nickell [##REF##12172763##17##] followed (mean
follow-up of 3.7 years) 66 children (mean age at stop of antibiotics = 4.4
years for the girls and 3.1 years for the boys) considered at risk for UTI
(including 48 children with VUR) after completion of the initial course of
prophylactic antibiotics. During the initial course of prophylactic antibiotics,
16 children presented with UTIs, with voiding dysfunction and abnormal
kidney(s) being identified as risk factors for these infections. Twenty-eight
children had UTI during the follow-up period, but 13 of these children were
receiving an antibiotic at the time of the infection. Voiding dysfunction was
again identified as a risk factor for infection in this time period.</p> <p>Al-Sayyad et al. [##REF##16148658##18##] also performed a
retrospective chart review of 78 children of 4 years or older with persistent
VUR (mean age at stop of antibiotics = 5.7 years) and with reflux grade less than
IV and normal voiding pattern or mild voiding dysfunction, who were taken off
antibiotic prophylaxis (mean follow-up off antibiotics = 37.7 months). UTI
developed in 9 children (11.5%): 8 cases of cystitis and 1 case of clinically
presumptive pyelonephritis. None of the children had new renal scarring
detected on renal ultrasound.</p> <p>Fifty-four children (mean age at stop of
antibiotics = 6 years) with persistent VUR (all grades, but only 2 patients had
high-grade reflux IV or V at the stop of antibiotics) were followed
prospectively after discontinuation of antibiotic prophylaxis (mean follow-up
off antibiotics = 4.4 years) in the study by Georgaki-Angelaki et al. [##REF##16308218##19##]. All
these children were old enough to describe symptoms of UTI, and had normal
voiding patterns, kidneys without hydronephrosis or new scar lesions, and a
period of at least 2 years without UTI. The number of symptomatic UTI episodes
was similar during the on- and off-prophylaxis periods: 9 (cystitis 3 and
pyelonephritis 6) and 8 episodes (cystitis 1 and pyelonephritis 7),
respectively. No new scars were detected by DMSA scan at the end of the
prophylaxis period (50 children tested) and at the end of the follow-up period
(33 children tested). In none of the children, renal function deteriorated.</p> <title>3.2. Antibiotic prophylaxis versus intermittent therapy of episodes of urinary tract infection</title> <p>The small studies by Reddy et al. [##UREF##2##20##] and
Craig et al. [##UREF##3##21##] were the first to compare antibiotic prophylaxis with no
treatment. In the study by Reddy et al. [##UREF##2##20##], 43 children with VUR were
randomly assigned to one of three groups: daily urine nitrate tests without
antibiotic prophylaxis (surveillance), daily urine nitrate tests with
antibiotic prophylaxis 3 times a week (intermittent prophylaxis), or daily
antibiotic prophylaxis (continuous prophylaxis). The incidence of UTI in the 3
groups was as follows: 1/13, 2/14, and 5/16 in the continuous prophylaxis,
intermittent prophylaxis, and surveillance groups, respectively.</p> <p>In the study by Craig et al. [##UREF##3##21##], 41 children
under 3 months of age with asymptomatic VUR received antibiotic prophylaxis
(cotrimoxazole for 3 years) or placebo. Two children in the placebo group
(<italic>n</italic> = 20) and no child in the antibiotic group (<italic>n</italic> = 21) developed UTI, and none of
the children developed new renal damage on DMSA scan.</p> <p>The multicenter study of Garin et al. [##REF##16510640##22##]
evaluated the role of VUR in causing UTI and renal parenchymal damage in 218
patients after an episode of acute pyelonephritis, and determined whether
antibiotic prophylaxis (nitrofurantoin or cotrimoxazole for 1 year) could prevent
UTI and renal parenchymal damage in the subgroup of patients with mild or
moderate VUR (grades I–III). After 1
year of follow-up, the presence of VUR did not significantly increase the incidence
of UTI or renal scarring on DMSA scan. Among the 113 patients with VUR,
antibiotic prophylaxis did not result in a clinical advantage to prevent UTI (23.6%
on versus 22.4% off prophylaxis) or renal scars (9% on versus 3.4% off
prophylaxis). Ironically, recurrent acute pyelonephritis was more frequent in
the intervention group than in the control group (12.9% on versus 1.7% off
prophylaxis) and in all 7 cases, while on antibiotics the offending bacteria
showed resistance to the used antibiotic.</p> <p>In the updated meta-analysis for the Cochrane
Database of Systematic Reviews [##UREF##4##26##], the authors stated that the studies by
Reddy et al. [##UREF##2##20##] and Garin et al. [##REF##16510640##22##] were unable to demonstrate a difference
in the risk for UTI or renal parenchymal damage between intervention and control
groups, and also that differences cannot be excluded because of the small number
of patients studied so far. Furthermore, they concluded that combined therapy
(antibiotic prophylaxis plus surgery) offers no advantages over antibiotic
prophylaxis alone in terms of risk for UTI or renal parenchymal damage.</p> <p>Conway et al. [##REF##17622599##23##] studied a cohort of 611
children aged 6 years or younger with a first episode of UTI and without
significant comorbidity to identify risk factors for recurrent UTI and examine
the effect of antibiotic prophylaxis on recurrent UTI. Age of 3–5 years and high
grade of reflux (IV or V) were identified as risk factors for recurrent UTI;
the impact of voiding pattern was not evaluated in this study. They found that
antibiotic prophylaxis had no significant effect on the risk of recurrence of
UTI (hazard ratio of 1.01), even when stratified by type of antibiotic and
stratified for covariates such as sex, race, age, and result of VCUG. Among the
83 children with recurrent UTI, a nested case-control study was performed to
determine risk factors for isolation of resistant bacteria. Antibiotic
prophylaxis clearly increased the likelihood of the infection being caused by a
resistant pathogen (odds ratio of 7.50).</p> <p>A French multicenter study by Roussey-Kesler et
al. [##REF##18082208##24##] evaluated whether antibiotic prophylaxis (cotrimoxazole for 18 months)
could reduce the recurrence of UTI in 225 young children with grade I, II, or III
VUR. Eighteen months later, recurrence of all UTIs and febrile UTIs was not
significantly different between the intervention and control groups: 17% versus
26% (<italic>P</italic> = .15) and 13% versus 16% (<italic>P</italic> = .52), respectively. When
patients with grades I–III reflux were
analyzed separately, again no significant differences were observed (<italic>P</italic> = .22, <italic>P</italic> = .23, and <italic>P</italic> = .57, resp.). However, prophylaxis
significantly reduced UTI in boys (<italic>P</italic> = .013) but not in girls (<italic>P</italic> = .8), and then only in those boys with grade III VUR (<italic>P</italic> = .04).</p> <p>Finally, an Italian multicenter study by
Pennesi et al. [##REF##18490378##25##] assessed the effectiveness of antibiotic prophylaxis (cotrimoxazole
for 2 years) in preventing pyelonephritis and in avoiding the occurrence of new
scars in 100 children with grade II, III, or IV VUR at first episode of
pyelonephritis, who were younger than 30 months. After 2 years of follow-up, 18
children (36%) in the intervention group and 15 children (30%) in the control
group had at least 1 pyelonephritis recurrence. Thus, the risk for having at
least 1 pyelonephritis recurrence was even slightly higher in the intervention
group than in the control group (relative risk of 1.2). While all episodes of
pyelonephritis in the control group were caused by sensitive strains of <italic>Escherichia coli</italic>, multiresistant
bacteria (all resistant to cotrimoxazole among other antibiotics) were
responsible for all infections in the intervention group. Furthermore, the
presence of renal scars on DMSA scan was the same in children with or without
antibiotic prophylaxis (relative risk of 1.2).</p> <p>According to the recently revised NICE guideline,
antibiotic prophylaxis is not routinely recommended in children after first-time
UTI, and should only be considered after recurrent UTI [##UREF##1##12##, ##REF##17717369##13##].</p>
<title>3. RESULTS AND DISCUSSION</title> <p>Long-term antibiotic prophylaxis remains a
common practice in the management of children with VUR. The most commonly used
drugs are nitrofurantoin, cotrimoxazole, amoxicillin, and cephalosporins [##REF##11391331##29##, ##REF##16510674##30##].
However, these medications may cause side effects and promote the development
of resistant bacteria [##REF##16510640##22##, ##REF##17622599##23##, ##REF##18490378##25##, ##REF##16203936##31##]. Furthermore, the optimal duration of
prophylaxis and optimal (low) dose of antibiotic are unclear, and compliance with
this long-term treatment is not always assured.</p> <p>In the 1960's, animal data showed that a UTI in
the presence of VUR can cause renal damage. It was then hypothesized that
sterilization of the urine could prevent pyelonephritis, and thereby also the
resulting parenchymal damage.</p> <p>At the end of the 1970's, two very small
studies indeed suggested that prophylactic antibiotics may prevent recurrent
UTIs in children, particularly during the period of prophylaxis. Smellie et al.
[##UREF##6##32##] compared 6–12 months of
antibiotic prophylaxis (cotrimoxazole or nitrofurantoin) versus no treatment in
53 children with acute UTI. None of the children in the intervention group had
a UTI during the prophylaxis period, while 11 children in the control group
presented with a UTI. Twelve months after stopping prophylactic antibiotics, 8
children (32%) in the intervention group compared with 13 (64%) in the control
group had suffered from a recurrent UTI.</p> <p>Lohr et al. [##REF##322082##33##] performed a crossover study on
18 girls with a history of at least 3 episodes of bacteriuria in the previous
year (including 1 girl with VUR). Each child was placed on nitrofurantoin for 6
months and on placebo for a similar period. There were 35 episodes of
bacteriuria (4.2 episodes/patient/year) in
the patients taking the placebo versus 2 episodes (0.2 episodes/patient/year) in the children
taking the antibiotic. Fourteen symptomatic UTIs (1.7 episodes/patient/year) occurred during the
placebo periods, and none during the prophylaxis periods.</p> <p>In 1997, the Pediatric Vesicoureteral Reflux
Guidelines Panel of the American Urological Association (AUA) recommended
continuous antibiotic prophylaxis as initial therapy for children with reflux
grades I–IV [##REF##9112544##28##]. However,
this recommendation was based on expert opinion rather than on clear scientific
evidence.</p> <title>3.1. Discontinuation of antibiotic prophylaxis</title> <p>During the following decades, this therapeutic
practice has been challenged on multiple occasions. First, several authors
demonstrated that in certain circumstances antibiotic prophylaxis can be safely
discontinued.</p> <p>Cooper et al. [##REF##10604374##15##] discontinued antibiotic
prophylaxis in 51 children with persistent primary VUR (grades I–IV). All children
were old enough to describe the symptoms of UTI (mean age at stop of
antibiotics = 8.6 years), and had a minimal or questionable history of true UTI,
normal voiding patterns, and kidneys with no significant hydronephrosis or
scars. A retrospective chart review revealed 6 episodes (11.8%) of UTI after
cessation of prophylaxis (mean follow-up off antibiotics = 3.7 years): 1 case
of cystitis and 5 cases of clinically presumptive pyelonephritis. None of the
children showed new renal scars on renal ultrasound. However, it should be
noted that renal ultrasound has low sensitivity for detection of renal scars.</p> <p>The retrospective chart review by Thompson et
al. [##REF##11547114##16##] of 196 children (mean age at stop of antibiotics = 6 years) who had
been withdrawn from prophylactic antibiotics (mean follow-up off antibiotics =
3.4 years) despite persistent reflux (all grades) showed a similar rate of UTIs
per patient/year on
or off antibiotics (0.29 on versus 0.24 off). Paradoxically, for the 39
children with high-grade reflux IV or V, there was a difference in the rate of
UTIs per patient/year
seemingly in favor of discontinuation of antibiotic prophylaxis (0.39 on versus
0.18 off). In addition, the rate of new
renal scarring on DMSA scan after stop of antibiotics was comparable with the
rate during prophylaxis (2.6% on versus 3.6% off).</p> <p>Hellerstein and Nickell [##REF##12172763##17##] followed (mean
follow-up of 3.7 years) 66 children (mean age at stop of antibiotics = 4.4
years for the girls and 3.1 years for the boys) considered at risk for UTI
(including 48 children with VUR) after completion of the initial course of
prophylactic antibiotics. During the initial course of prophylactic antibiotics,
16 children presented with UTIs, with voiding dysfunction and abnormal
kidney(s) being identified as risk factors for these infections. Twenty-eight
children had UTI during the follow-up period, but 13 of these children were
receiving an antibiotic at the time of the infection. Voiding dysfunction was
again identified as a risk factor for infection in this time period.</p> <p>Al-Sayyad et al. [##REF##16148658##18##] also performed a
retrospective chart review of 78 children of 4 years or older with persistent
VUR (mean age at stop of antibiotics = 5.7 years) and with reflux grade less than
IV and normal voiding pattern or mild voiding dysfunction, who were taken off
antibiotic prophylaxis (mean follow-up off antibiotics = 37.7 months). UTI
developed in 9 children (11.5%): 8 cases of cystitis and 1 case of clinically
presumptive pyelonephritis. None of the children had new renal scarring
detected on renal ultrasound.</p> <p>Fifty-four children (mean age at stop of
antibiotics = 6 years) with persistent VUR (all grades, but only 2 patients had
high-grade reflux IV or V at the stop of antibiotics) were followed
prospectively after discontinuation of antibiotic prophylaxis (mean follow-up
off antibiotics = 4.4 years) in the study by Georgaki-Angelaki et al. [##REF##16308218##19##]. All
these children were old enough to describe symptoms of UTI, and had normal
voiding patterns, kidneys without hydronephrosis or new scar lesions, and a
period of at least 2 years without UTI. The number of symptomatic UTI episodes
was similar during the on- and off-prophylaxis periods: 9 (cystitis 3 and
pyelonephritis 6) and 8 episodes (cystitis 1 and pyelonephritis 7),
respectively. No new scars were detected by DMSA scan at the end of the
prophylaxis period (50 children tested) and at the end of the follow-up period
(33 children tested). In none of the children, renal function deteriorated.</p> <title>3.2. Antibiotic prophylaxis versus intermittent therapy of episodes of urinary tract infection</title> <p>The small studies by Reddy et al. [##UREF##2##20##] and
Craig et al. [##UREF##3##21##] were the first to compare antibiotic prophylaxis with no
treatment. In the study by Reddy et al. [##UREF##2##20##], 43 children with VUR were
randomly assigned to one of three groups: daily urine nitrate tests without
antibiotic prophylaxis (surveillance), daily urine nitrate tests with
antibiotic prophylaxis 3 times a week (intermittent prophylaxis), or daily
antibiotic prophylaxis (continuous prophylaxis). The incidence of UTI in the 3
groups was as follows: 1/13, 2/14, and 5/16 in the continuous prophylaxis,
intermittent prophylaxis, and surveillance groups, respectively.</p> <p>In the study by Craig et al. [##UREF##3##21##], 41 children
under 3 months of age with asymptomatic VUR received antibiotic prophylaxis
(cotrimoxazole for 3 years) or placebo. Two children in the placebo group
(<italic>n</italic> = 20) and no child in the antibiotic group (<italic>n</italic> = 21) developed UTI, and none of
the children developed new renal damage on DMSA scan.</p> <p>The multicenter study of Garin et al. [##REF##16510640##22##]
evaluated the role of VUR in causing UTI and renal parenchymal damage in 218
patients after an episode of acute pyelonephritis, and determined whether
antibiotic prophylaxis (nitrofurantoin or cotrimoxazole for 1 year) could prevent
UTI and renal parenchymal damage in the subgroup of patients with mild or
moderate VUR (grades I–III). After 1
year of follow-up, the presence of VUR did not significantly increase the incidence
of UTI or renal scarring on DMSA scan. Among the 113 patients with VUR,
antibiotic prophylaxis did not result in a clinical advantage to prevent UTI (23.6%
on versus 22.4% off prophylaxis) or renal scars (9% on versus 3.4% off
prophylaxis). Ironically, recurrent acute pyelonephritis was more frequent in
the intervention group than in the control group (12.9% on versus 1.7% off
prophylaxis) and in all 7 cases, while on antibiotics the offending bacteria
showed resistance to the used antibiotic.</p> <p>In the updated meta-analysis for the Cochrane
Database of Systematic Reviews [##UREF##4##26##], the authors stated that the studies by
Reddy et al. [##UREF##2##20##] and Garin et al. [##REF##16510640##22##] were unable to demonstrate a difference
in the risk for UTI or renal parenchymal damage between intervention and control
groups, and also that differences cannot be excluded because of the small number
of patients studied so far. Furthermore, they concluded that combined therapy
(antibiotic prophylaxis plus surgery) offers no advantages over antibiotic
prophylaxis alone in terms of risk for UTI or renal parenchymal damage.</p> <p>Conway et al. [##REF##17622599##23##] studied a cohort of 611
children aged 6 years or younger with a first episode of UTI and without
significant comorbidity to identify risk factors for recurrent UTI and examine
the effect of antibiotic prophylaxis on recurrent UTI. Age of 3–5 years and high
grade of reflux (IV or V) were identified as risk factors for recurrent UTI;
the impact of voiding pattern was not evaluated in this study. They found that
antibiotic prophylaxis had no significant effect on the risk of recurrence of
UTI (hazard ratio of 1.01), even when stratified by type of antibiotic and
stratified for covariates such as sex, race, age, and result of VCUG. Among the
83 children with recurrent UTI, a nested case-control study was performed to
determine risk factors for isolation of resistant bacteria. Antibiotic
prophylaxis clearly increased the likelihood of the infection being caused by a
resistant pathogen (odds ratio of 7.50).</p> <p>A French multicenter study by Roussey-Kesler et
al. [##REF##18082208##24##] evaluated whether antibiotic prophylaxis (cotrimoxazole for 18 months)
could reduce the recurrence of UTI in 225 young children with grade I, II, or III
VUR. Eighteen months later, recurrence of all UTIs and febrile UTIs was not
significantly different between the intervention and control groups: 17% versus
26% (<italic>P</italic> = .15) and 13% versus 16% (<italic>P</italic> = .52), respectively. When
patients with grades I–III reflux were
analyzed separately, again no significant differences were observed (<italic>P</italic> = .22, <italic>P</italic> = .23, and <italic>P</italic> = .57, resp.). However, prophylaxis
significantly reduced UTI in boys (<italic>P</italic> = .013) but not in girls (<italic>P</italic> = .8), and then only in those boys with grade III VUR (<italic>P</italic> = .04).</p> <p>Finally, an Italian multicenter study by
Pennesi et al. [##REF##18490378##25##] assessed the effectiveness of antibiotic prophylaxis (cotrimoxazole
for 2 years) in preventing pyelonephritis and in avoiding the occurrence of new
scars in 100 children with grade II, III, or IV VUR at first episode of
pyelonephritis, who were younger than 30 months. After 2 years of follow-up, 18
children (36%) in the intervention group and 15 children (30%) in the control
group had at least 1 pyelonephritis recurrence. Thus, the risk for having at
least 1 pyelonephritis recurrence was even slightly higher in the intervention
group than in the control group (relative risk of 1.2). While all episodes of
pyelonephritis in the control group were caused by sensitive strains of <italic>Escherichia coli</italic>, multiresistant
bacteria (all resistant to cotrimoxazole among other antibiotics) were
responsible for all infections in the intervention group. Furthermore, the
presence of renal scars on DMSA scan was the same in children with or without
antibiotic prophylaxis (relative risk of 1.2).</p> <p>According to the recently revised NICE guideline,
antibiotic prophylaxis is not routinely recommended in children after first-time
UTI, and should only be considered after recurrent UTI [##UREF##1##12##, ##REF##17717369##13##].</p>
<title>4. CONCLUSION</title> <p>Despite the lack of evidence for its
effectiveness, long-term antibiotic prophylaxis has been a common practice in
the management of children with VUR for decades. However, several uncontrolled
studies (total of 379 children) indicate that antibiotic prophylaxis can safely
be discontinued in a subset of patients, that is, school-aged children with low-grade
VUR, normal voiding patterns, kidneys without hydronephrosis or scars, and
normal anatomy of the urogenital system.</p> <p>More importantly, several recent RCTs suggest
that antibiotic prophylaxis (with cotrimoxazole) offers no advantage over intermittent
antibiotic therapy of UTIs in terms of prevention of recurrent UTIs or new
renal damage. However, further research is still warranted in view of the
limited number of children (total of 522 children) studied in these five RCTs.
Furthermore, children with high-grade VUR have generally been excluded from
these studies, and these findings cannot therefore be generalized. Finally, one
of the RCTs indicates that boys with grade III VUR benefit from antibiotic
prophylaxis, and there is a possibility that other subsets of patients, who will
benefit from prophylaxis, will be identified in the future.</p>
<p>Recommended by Hiep Nguyen</p> <p>The main goal of the management of vesicoureteral reflux (VUR) is prevention of recurrent urinary tract infections (UTIs), and thereby prevention of renal parenchymal damage possibly ensuing from these infections. Long-term antibiotic prophylaxis is common practice in the management of children with VUR, as recommended in 1997 in the guidelines of the American Urological Association. We performed a systematic review to ascertain whether antibiotics can be safely discontinued in children with VUR and whether prophylaxis is effective in the prevention of recurrent UTIs and renal damage in these patients. Several uncontrolled studies indicate that antibiotic prophylaxis can be discontinued in a subset of patients, that is, school-aged children with low-grade VUR, normal voiding patterns, kidneys without hydronephrosis or scars, and normal anatomy of the urogenital system. Furthermore, a few recent randomized controlled trials suggest that antibiotic prophylaxis offers no advantage over intermittent antibiotic therapy of UTIs in terms of prevention of recurrent UTIs or new renal damage.</p>
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Adv Urol. 2008 Jul 29; 2008:217805