Prophylaxis After First Febrile Urinary Tract Infection in Children?

A
Multicenter, Randomized, Controlled, Noninferiority Trial
Giovanni Montini, Luca Rigon, Pietro Zucchetta, Federica Fregonese, Antonella
Toffolo, Daniela Gobber, Diego Cecchin, Luigi Pavanello, Pier Paolo Molinari,
Francesca Maschio, Sergio Zanchetta, Walburga Cassar, Luca Casadio, Carlo
Crivellaro, Paolo Fortunati, Andrea Corsini, Alessandro Calderan, Stefania
Comacchio, Lisanna Tommasi, Ian K. Hewitt, Liviana Da Dalt, Graziella Zacchello,
Roberto Dall'Amico and on behalf of the IRIS group
Pediatrics 2008;122;1064-1071
DOI: 10.1542/peds.2007-3770

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/122/5/1064

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ARTICLE

Prophylaxis After First Febrile Urinary Tract

Infection in Children? A Multicenter, Randomized,
Controlled, Noninferiority Trial
Giovanni Montini, MDa, Luca Rigon, MDa, Pietro Zucchetta, MDb, Federica Fregonese, MDc, Antonella Toffolo, MDd, Daniela Gobber, MDe,
Diego Cecchin, MDb, Luigi Pavanello, MDf, Pier Paolo Molinari, MDg, Francesca Maschio, MDh, Sergio Zanchetta, MDi, Walburga Cassar, MDj,
Luca Casadio, MDk, Carlo Crivellaro, MDl, Paolo Fortunati, MDm, Andrea Corsini, MDn, Alessandro Calderan, MDo, Stefania Comacchio, MDa,
Lisanna Tommasi, MDa, Ian K. Hewitt, MBBSa, Liviana Da Dalt, MDp, Graziella Zacchello, MDa, Roberto Dall’Amico, MD, PhDq, on behalf of the
IRIS group

Departments of aPediatric Nephrology, bNuclear Medicine, and cPediatrics, eEpidemiology Unit, and pPediatric Emergency Department, Azienda Ospedaliera-University
of Padua, Italy; Pediatric Unit, dOderzo, fCastelfranco Veneto, gBologna, hMestre-Venezia, iSoave, jBolzano, kRavenna, lPiove di Sacco-Chioggia, mVerona-Borgo Trento,
nBentivoglio, and qThiene, Italy; oGeneral Practitioner, San Donà di Piave-Venezia, Italy

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

Antibiotic prophylaxis has been widely used after a febrile urinary tract infection, despite Antibiotic prophylaxis, commonly used to reduce the risk for repeat febrile urinary tract
the evidence supporting that its efficacy is weak. infections, does not reduce the rate of recurrence during 12 months after the first epi-
sode in children with or without the presence of primary nonsevere reflux.

ABSTRACT
OBJECTIVES. Febrile urinary tract infections are common in children and associated with
the risk for renal scarring and long-term complications. Antimicrobial prophylaxis
has been used to reduce the risk for recurrence. We performed a study to determine www.pediatrics.org/cgi/doi/10.1542/
peds.2007-3770
whether no prophylaxis is similar to antimicrobial prophylaxis for 12 months in
reducing the recurrence of febrile urinary tract infections in children after a first doi:10.1542/peds.2007-3770
febrile urinary tract infection. This trial has been registered at
www.clinicaltrials.gov (identifier
METHODS. The study was a controlled, randomized, open-label, 2-armed, noninferiority NCT00156546).
trial comparing no prophylaxis with prophylaxis (co-trimoxazole 15 mg/kg per day Key Words
urinary tract infection, antibiotic
or co-amoxiclav 15 mg/kg per day) for 12 months. A total of 338 children who were
prophylaxis, renal scar, DMSA scan
aged 2 months to ⬍7 years and had a first episode of febrile urinary tract infection
Abbreviations
were enrolled: 309 with a confirmed pyelonephritis on a technetium 99m dimer- UTI— urinary tract infection
captosuccinic acid scan with or without reflux and 27 with a clinical pyelonephritis RR—relative risk
and reflux. The primary end point was recurrence rate of febrile urinary tract CI— confidence interval
VUR—vesicoureteral reflux
infections during 12 months. Secondary end point was the rate of renal scarring ITT—intention-to-treat
produced by recurrent urinary tract infections on technetium 99m dimercaptosuc- DMSA— dimercaptosuccinic acid
cinic acid scan after 12 months. VCUG—voiding cystourethrography
IQR—interquartile range
RESULTS. Intention-to-treat analysis showed no significant differences in the primary Accepted for publication Mar 3, 2008
outcome between no prophylaxis and prophylaxis: 12 (9.45%) of 127 vs 15 (7.11%) Address correspondence to Giovanni
of 211. In the subgroup of children with reflux, the recurrence of febrile urinary tract Montini, MD, Nephrology, Dialysis and
Transplant Unit, Pediatric Department,
infections was 9 (19.6%) of 46 on no prophylaxis and 10 (12.1%) of 82 on Azienda Ospedaliera-University of Padova,
prophylaxis. No significant difference was found in the secondary outcome: 2 (1.9%) Via Giustiniani, 3, 35128 Padova, Italy.
of 108 on no prophylaxis versus 2 (1.1%) of 187 on prophylaxis. Bivariate analysis E-mail: montini@pediatria.unipd.it
and Cox proportional hazard model showed that grade III reflux was a risk factor for PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
recurrent febrile urinary tract infections. Whereas increasing age was protective, use American Academy of Pediatrics
of no prophylaxis was not a risk factor.
CONCLUSIONS. For children with or without primary nonsevere reflux, prophylaxis does not reduce the rate of recurrent
febrile urinary tract infections after the first episode. Pediatrics 2008;122:1064–1071

F EBRILE URINARY TRACT infections (UTIs) are considered the most common serious bacterial infections that occur
in infancy and early childhood in the developed world.1 Fifteen percent of cases are associated with renal
scarring,2 which is responsible for the long-term medical consequences (proteinuria, hypertension, chronic kidney
damage).3–5 The frequency of reinfection during the first year after a UTI has been estimated to be up to 30%.6–8
Antibiotic prophylaxis has been widely used despite the evidence supporting its efficacy is weak.

1064 MONTINI et al
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 In 3 studies (n ⫽ 153) from the 1970s, long-term (10
weeks to 12 months) antibiotics reduced the risk for
repeat positive urine cultures (relative risk [RR]: 0.4
[95% confidence interval (CI): 0.26 – 0.62]) compared
with placebo or no prophylaxis.9–11 Only 1 study re-
ported an increased risk (RR: 1.93 [95% CI: 0.63–5.92])
of recurrence of symptomatic UTI in 27 children who
received prophylaxis versus 32 children who received
placebo.9 In these 3 trials, the study population (mainly
girls and few patients with urinary tract abnormalities)
was small and did not reflect the pediatric population to
whom prophylaxis is usually given. Bacterial resistance
was not considered.
In 1 randomized study,12 the role of prophylaxis in
reducing the frequency of UTIs among patients with
acute pyelonephritis was not supported. This trial
showed that the use of antibiotic prophylaxis was not
only ineffective but also harmful: among children with
vesicoureteral reflux (VUR), recurrent acute UTIs was
observed for 7 of 55 patients who received urinary an-
tibiotic prophylaxis, compared with only 1 of the 58
patients with no prophylaxis (P ⫽ .0291). In all of the 7
cases, the offending bacteria showed resistance to the
antibiotic used for prophylaxis. In this study, the anti-
microbial treatment of the acute episode was not stan-
dardized, intention-to-treat (ITT) analysis was not per-
formed, and the age range was extremely wide. We
conducted a noninferiority, randomized, controlled trial
to determine whether no prophylaxis for children who
were aged 2 months to 7 years and had a first febrile UTI,
with or without the presence of primary nonsevere VUR,
is similar to antimicrobial prophylaxis for 12 months in
producing the recurrence of febrile UTIs.
METHODS
The study is a controlled, randomized, multicenter,
open-labeled, parallel-group trial. It was originally de-
signed as a 3-arm trial subsequently amended to be a
2-arm noninferiority study. It was conducted from May
2000 to August 2006 at 22 pediatric units located in
Northeast Italy, coordinated by the Unit of Nephrology,
Dialysis and Transplantation of the Pediatric Department
of Padova. The ethics committee of each participating
center approved the protocol. The parents of each child
signed an informed consent before participation.
Patient Inclusion and Exclusion Criteria
The study population was recruited among children who
had a first episode of febrile UTI, with or without pri-
mary nonsevere VUR (first to third degree). Recruitment
was confined to children who were aged 2 months to 7
years and had normal renal function.13 Exclusion criteria
were complex urologic malformations and/or severe re-
nal damage (dimercaptosuccinic acid [DMSA] scintigra-
phy showing a relative function of 1 kidney ⬍30%).
The diagnosis of first febrile UTI at presentation was
made by fever ⱖ38°C, pyuria (2 concordant consecutive
test results with white cell counts ⱖ25/␮L), and urine
culture (2 concordant consecutive tests with growth of
only 1 microorganism ⱖ100 000 colony-forming units/
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mL). Urine was collected with a sterile urinary bag; the
2 concordant consecutive urinalysis and culture were
required to minimize the risk for false-positive tests.
Children also had to have at least 2 of fever ⱖ38°C,
raised inflammatory indices in the first 48 hours (eryth-
rocyte sedimentation rate ⱖ30 mm in the first hour or
C-reactive protein ⱖ3 times upper limit of normal val-
ues, or both), and neutrophil count above the normal
values for age.
Imaging Studies
Prerandomization
Ultrasonography and DMSA renal scans were performed
within 10 days from commencement of antibiotic for the
febrile UTI. Focal or diffuse areas of decreased uptake in
the first DMSA scan, without evidence of cortical loss,
were considered indicative of acute pyelonephritis.
Voiding cystourethrography (VCUG; radiology, with 1
filling) was performed within 2 months of UTI.
Postrandomization
Repeat DMSA scans were planned 12 months from ran-
domization, or, when a new episode of febrile UTI oc-
curred, at least 6 months after infection. Renal scarring
was defined as decreased uptake with distortion of the
contours or as cortical thinning with loss of parenchymal
volume. Two nuclear physicians, who were blinded to
the patients’ test results, interpreted the scans indepen-
dently. Discrepancies were resolved by discussion between
the assessors.
Antibiotic Treatment of Febrile UTI
Antibiotic treatment of the initial UTI was either intra-
venous ceftriaxone for 3 days followed by oral co-amoxi-
clav for 7 days or oral treatment only with co-amoxiclav
for 10 days. After completion of treatment, all children
were given prophylaxis until the VCUG was performed.
Randomization
The randomization scheme was computer-generated by
the coordinating center. Randomization, 1:1:1 for the 3
arms, was stratified by center, gender, and clinical group
on the basis of presence or absence of VUR and of the
parenchymal localization of the acute UTI. There were 3
groups: (1) acute positive DMSA without VUR, (2) acute
negative DMSA with VUR, and (3) acute positive DMSA
with VUR. Each participating center received 6 series
with allocation codes. The series were 1 for each stra-
tum, and each series contained 12 sealed, opaque enve-
lopes. Every envelope was numbered with a sequential
number. Each participating center assigned every en-
rolled child to a stratum (on the basis of gender and
clinical group). The allocation code for that child was
then assigned, opening the next envelope in that stra-
tum series.
In the second part of the study, the 1:1 randomization
scheme was automatically generated, stratified as before,
and kept centrally. After assigning the child to a stratum,
the centers received the allocation treatment from the
coordinating center. Investigator meetings to standard-
PEDIATRICS Volume 122, Number 5, November 2008 1065
ize good clinical practice were organized before and dur-
ing the study.
Study Interventions
Recruited patients were allocated to group A, no pro-
phylaxis, or group B, prophylaxis (co-trimoxazole or
co-amoxiclav both at the dosage of 15 mg/kg per day).
Outpatient urine cultures were performed monthly for
the first 6 months and then every 2 months; outpatient
clinic visits were at 6 and 12 months. A DMSA scheduled
at 12 months ended follow-up for all patients. Children
who experienced 2 recurrent febrile UTIs were switched
to prophylaxis when allocated to no prophylaxis and to
other antibiotic or referred for VUR surgery when al-
ready allocated to prophylaxis. Data collected were
symptoms and signs of UTI (urinalysis, urine culture),
compliance to treatment and adverse effects, and resis-
tance to the prophylactic antibiotic in case of positive
urine cultures. Compliance was evaluated by assessment
of antimicrobial activity in urine at the routine urine
cultures and by a questionnaire with a visual analogic
scale of parents’ assessment of “difficulty” in following
treatment.
Outcome Measurements
The primary end point was the first recurrence of febrile
UTIs in the 12 months after randomization. Recurrent
UTI was defined by presence of fever (⬎38°C), pyuria,
and urine culture as defined in the inclusion criteria.
Additional recurrences and arm switches were therefore
not accounted as “failure” per se.
Secondary end point was the rate of new renal scar-
ring defined as scarring, other than at the site of the
initial pyelonephritis, after 12 months. Exploratory anal-
yses were also performed to evaluate the risk for repeat
positive urine cultures and the rate of scarring at the site
of the initial infection as potential end points.
Study Design and Sample Size
The study was designed as a controlled, randomized,
open-label, 3-armed, parallel-group study, comparing
no prophylaxis, prophylaxis with co-trimoxazole, and
prophylaxis with co-amoxiclav. A first comparison was
planned between no prophylaxis and prophylaxis, with
a subsequent comparison between the 2 antibiotics if the
pooling of prophylaxis had shown a better outcome.
The study aimed to enroll 660 patients in a 1:1:1 ratio
across the 3 groups. Enrollment was slower than antic-
ipated, reaching 237 patients by August 2003 (evenly
allocated to no prophylaxis, co-trimoxazole, and co-
amoxiclav). Thus, following the recommendation of the
Data and Safety Monitoring Committee to take action to
be able to complete enrollment in a reasonable time
frame, we decided to modify the study design, maintain-
ing the primary objective (comparison between prophy-
laxis and no prophylaxis) and abandoning the compar-
ison between the 2 antibiotics regimens.
The new sample size for the 2-arm, noninferiority
trial was calculated to be 313 patients (rounded to 340,
for possible dropouts), setting power at 70% and ␣ error
1066 MONTINI et al
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of .05 (1-sided), maintaining the assumption of 20%
incidence of recurrence, and considering an upper con-
fidence limit of 30% for noninferiority for the no-pro-
phylaxis arm. The patients who were enrolled after the
amendment were randomly assigned in a 1:1 ratio be-
tween no prophylaxis and prophylaxis, with a final ex-
pected ratio of 1:1.5.
Statistical Analysis
In the ITT analysis, 2 scenarios were considered for
patients who exited the trial (lost to follow-up): (1) all
“failures” and (2) all “successes.” The efficacy compari-
son between “prophylaxis” and “no prophylaxis” was
performed considering the differences between treat-
ments and the 95% CI for this difference. The binomial
outcome measures were tested using the ␹2 test (Fisher
test and Pearson test); the numerical outcome measures
were tested using Student’s t test or the Mann-Whitney
test, as appropriate. A multivariate survival analysis was
conducted using the Cox proportional hazards model.
The survival analyses conducted using the Cox propor-
tional hazards model have been integrated with the
evaluation of Kaplan-Meier curves, log-rank tests.
and/or Wilcoxon’s test to detect significant differences in
the curves. The number of patients to be treated was
calculated as previously suggested.14
The software Stata 9.0 (Stata Corp, College Station,
TX) was used for the statistical analysis. A secondary
analysis comparing the effectiveness of the prophylactic
treatment in subgroups of patients defined by age, gen-
der, and grade of reflux was performed.
RESULTS
Between July 2000 and September 2005, 22 centers
enrolled and randomly assigned 338 patients: 127
(37.6%) to no prophylaxis and 211 (62.4%) to pro-
phylaxis (113 [54%] co-amoxiclav and 98 [46%] co-
trimoxazole). The final randomization ratio was 1:1.7
(expected 1:1.5). Follow-up was completed in August
2006. Three patients were wrongly enrolled (2 did not
complete the screening work out; 1 older than 7
years). Adherence to the protocol was good: 26 pa-
tients who were lost to follow-up were evenly distrib-
uted in the 2 arms (10 [7.9%] of 127 and 16 [7.6%] of
211). Patient allocation and compliance to protocol
are shown in Fig 1.
The acute infection was treated with initial intrave-
nous antibiotics for 151 (45%) patients and with com-
plete oral treatment for 183 (55%), unknown in 4. The
distribution of oral and intravenous treatment was sim-
ilar in the 2 arms (P ⫽ .22). All children were given a
prophylactic regimen of co-amoxiclav until VCUG was
performed for a median (interquartile range [IQR]) pe-
riod of 40 days (33–50); no prophylaxis: 40 (32–51);
prophylaxis: 41 (34 –50). Baseline characteristics were
similar for children who were randomly assigned in the
2 arms (Table 1).
Primary Outcome
Febrile UTIs were not significantly different between
the 2 groups during follow-up: 12 (9.45%) of 127 in the
 Pts with a recent febrile UTI:

N = 338

Randomization

No prophylaxis n = 127 (37.6%)

Prophylaxis n = 211 (62.4%)
Acute DMSA + and VUR I-III, n = 35
Acute DMSA + and no VUR, n = 77 Acute DMSA + and VUR I-III, n = 70
Acute DMSA - and VUR I-III, n = 14 Acute DMSA + and no VUR, n = 127
Acute DMSA - and VUR I-III, n = 13
1 missing data
1 missing data

LTFU: LTFU:
0−12 mo: 10 (7.9%) 0–12 mo: 16 (7.6%)

FIGURE 1
Patient flowchart.

Primary outcome: recurrence of Primary outcome: recurrence of

febrile UTI 0_12 mo: febrile UTI 0_12 mo:

n = 12/127 (9.5%) ITT, if LTFU = no recurrence n = 15/211 (7.1%) ITT, if LTFU = no recurrence
n = 22/127 (17.3%) ITT, if LTFU = recurrence n = 31/211 (14.7%) ITT, if LTFU = recurrence

n = 12/117 (10.2%), OT n = 15/195 (7.6%), OT

Exploratory analysis: repeat positive Exploratory analysis: repeat positive

urine culture: urine culture:
n = 24/127 (18.9%) n = 21/211 (10.0%)

Not performed DMSA at 1 Not performed DMSA at 1

y/n patients on follow-up: y/n patients on follow-up:
9/117 (7.7%) 8/195 (4.1%)

Secondary outcome: scars not at the site of Secondary outcome: scars not at the site of
original pyelonephritis at 12 mo: original pyelonephritis at 12 mo:

n = 2/108 (1.9%) n = 2/187 (1.1%)

18

no-prophylaxis group and 15 (7.11%) of 211 (risk dif-
ference: 2.34% [95% CI: 3.8%– 8.4%]; Table 2). These
results hold true even once patients are stratified by
grade of VUR (Table 2). These data were obtained with
ITT analysis, considering the patients lost to follow-up
before the 12-month visit as having no recurrence. Data
are shown also as a Kaplan-Meier for time free of events
in Fig 2. Median time (IQR) to febrile recurrences was
113 days (57–192) with no significant difference be-
tween the 2 groups (log-rank test P ⫽ .36). We found
similar results when we counted all patients who were
lost to follow-up as having a recurrence during the 12
months and with an on-treatment analysis (Table 2).
The exploratory analysis showed that the rate of repeat
positive urine culture and concomitant positive urinaly-
sis was significantly different between the 2 groups: 24
(18.9%) of 127 on no prophylaxis and 20 (9.5%) of 211
on prophylaxis (P ⫽ .02).
Age, gender, VUR grade, treatment of the initial UTI
(oral versus intravenous), and prophylaxis were consid-
ered in bivariate analysis: younger age and VUR grade
were associated with recurrence of febrile UTI. The mean
age was 7.1 vs 14.6 months for children with recurrence
versus no recurrence (P ⫽ .02). The rate of recurrences
increased with the grade of VUR, from 8 (3.8%) of 210
for patients with no VUR to 2 (6.7%) of 30, 5 (8.6%) of
58, and 12 (30%) of 40 for patients with VUR grades I,
II, and III, respectively (P ⬍ .01). In the Cox proportional
hazards model, no prophylaxis was not a risk factor for
recurrence of febrile UTIs; older age was confirmed to be
protective and grade III reflux to be a risk factor (Table
3). The number of patients to be treated to prevent a
febrile recurrence was 41.7 children for 1 year.
Secondary Outcomes
A total of 87% (295) of enrolled patients had the DMSA
scan at 1 year with a median (IQR) time to DMSA of 351
days (329 –385) after enrollment. A new renal scar (in a
different site from the initial pyelonephritis) was found
in 4 (1.4%) of 295 patients (Table 2); the new scars

PEDIATRICS Volume 122, Number 5, November 2008 1067

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 TABLE 1 Baseline Characteristics TABLE 2 Primary and Secondary Outcomes in the Univariate
Characteristic No Prophylaxis Prophylaxis Analysis
Age, mo Parameter No Prophylaxis Mean Difference
Median (range) 10.2 (1–73) 10.6 (1–101) Prophylaxis (95% CI)
Mean (SD) 14.7 (15.5) 14.7 (15.5) Primary outcome
n 127 211 Febrile UTIs, n (%) 12/127 (9.5) 15/211 (7.1) 2.34 (⫺3.8 to 8.4)
Girls, n (%) 90/127 (70.9) 144/211 (68.5) (ITT with LTFU ⫽ no
Max body temperature, °C recurrence)
Median (range) 39.4 (37.5–40.5) 39.3 (36–41.5) VUR
Mean (SD) 39.30 (0.62) 39.30 (0.78) No 3/81 (3.7) 5/129 (3.9) ⫺0.2 (⫺5.5 to 5.1)
n 127 210 Yes 9/46 (19.6) 10/82 (12.1) 7.5 (⫺6.0 to 20.1)
WBC, ⫻ 109 cells/L 16.8 (2.7–52.1) 18.0 (3.8–42.1) VUR grade
Median (range) 18.0 (7.9) 18.2 (6.4) 1 1/11 (9.1) 1/19 (5.3) 3.8 (⫺15.6 to 23.6)
Mean (SD) 121 207 2 2/21 (9.1) 3/37 (8.1) 1.0 (⫺14.1 to 16.1)
n 3 6/14 (42.9) 6/26 (23.1) 19.8 (⫺10.8 to 50.4)
Neutrophils, ⫻ 109 cells/L 1 Primary outcome
Median (range) 9.4 (0.5–46.9) 0.7 (1.5–29.4) Febrile UTIs, n (%) 22/127 (17.3) 31/211 (14.7) 2.6 (⫺5.5 to 10.8)
Mean (SD) 10.9 (6.8) 11.2 (5.3) (ITT with LTFU ⫽
n 99 170 recurrence)
ESR, mm/h Primary outcome 12/117 (10.2) 15/195 (7.6) 2.6 (⫺4.0 to 9.2)
Median (range) 59 (0–150) 65 (0–115) Febrile UTIs, n (%)
Mean (SD) 60.0 (32.0) 62.0 (27.0) (OT)
n 50 91 Exploratory analysis
CRPa All positive culture 24/127 (18.9) 20/211 (9.5) 9.4 (1.5 to 17.3)
Median (range) 17 (0.5–70) 17 (1.0–113) Scar in a new site 2/108 (1.9) 2/187 (1.1) 0.8 (⫺2.1 to 3.7)
Mean (SD) 20.0 (13.0) 20.0 (16.0) Scar in the site of 31/108 (28.7) 48/187 (25.7) 3.0 (⫺7.6 to 13.6)
n 121 205 previous APN
APN antibiotic therapy, 52/127 (41) 99/207 (48)
LTFU indicates lost to follow-up; OT, on-treatment analysis; APN, Acute pyelonephritis.
intravenous/oral (%)
VUR grade, n (%)
0 81 (63.8) 129 (61.2)
1 11 (8.7) 19 (9.0)
2 21 (16.5) 37 (17.5)
3 14 (11.0) 26 (12.3)
WBC indicates white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein;
APN, acute pyelonephritis.
a Ratio between obtained value and upper limit of normal reference values for each laboratory.

occurred in 1 kidney without reflux, 1 kidney with grade

II reflux, and 2 kidneys with grade III reflux. No differ-
ence was found in no prophylaxis (2 [1.9%] of 108)
versus prophylaxis (2 [1.1%] of 187; risk difference:
0.8% [95% CI: ⫺2.1%–3.7%]). Similar results were
found in exploratory analysis, comparing the rate of
scars at the site of the first pyelonephritis: 31 (28.7%) of FIGURE 2
Kaplan-Meier curve of free time from event (febrile UTI).
108 vs 48 (25.7%) of 187 (Table 2) and when consider-
ing the rate of new scars in the children with recurrences
(2 [17%] of 12) for no prophylaxis and for prophylaxis 6 cases and P mirabilis, Enterobacter, and K pneumoniae in
(2 [13%] of 15). 1 case each.

Urine Cultures Other Antibiotics Used

A total of 2422 routine urine cultures and urinalyses
were performed. The cause of the 27 recurrences were
similar in the 2 groups and were attributed to Escherichia
coli in 19 (70%) of 27, Proteus mirabilis in 2 of 27 (7%),
Enterobacter in 2 of 27 (7%); Pseudomonas aeruginosa,
Klebsiella oxytoca, Klebsiella pneumoniae, and Citrobacter in
1 (4%) of 27 each. All but 1 of the 9 recurrences that
were attributed to resistant bacteria were in the prophy-
laxis group, and the 1 that occurred in the no-prophy-
laxis group was in a child who had been switched to
prophylaxis. The isolated resistant bacteria were E coli in
Forty-five of 338 patients changed allocated arm or an-
tibiotic: 9 allocated to no prophylaxis switched to pro-
phylaxis (7 because of UTI recurrence, 2 for unknown
reasons); 15 switched from co-amoxiclav to other anti-
biotics and 3 stopped; 12 switched from co-trimoxazole
to other antibiotics and 6 stopped. One patient under-
went surgery for VUR.
Adherence
A total of 340 of 851 urine cultures were tested for
antimicrobial activity in the no-prophylaxis and 578 of

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 TABLE 3 Analysis of Risk for Recurrence of Febrile UTIs febrile UTIs, makes it unlikely that the missing data
Characteristic Multivariate, HR P could influence the risk difference of the recurrence rate.
(95% CI) A weakness of our study is that it was not double-
blinded and placebo-controlled. We believe that the ac-
Gender
Male 1.00 (reference) tual design of our study does not permit major bias,
Female 1.90 (0.73 to 5.05) because the study has objective end points: the diagnosis
Age of recurrent UTI has precise criteria, patients and their
For each montha 0.93 (0.86 to 0.99) doctors were appropriately instructed to suspect recur-
VUR rent infections, and the presence of scar was evaluated
No VUR 1.00 (reference) blindly by 2 nuclear physicians.
VUR grade I 1.75 (0.37 to 8.27) The results of our study are in accordance with the
VUR grade II 1.87 (0.56 to 6.21) study by Garin et al12 in showing no benefit of prophy-
VUR grade III 7.58 (3.01 to 19.1) ⬍.01
laxis on no prophylaxis and in revealing higher preva-
Antibiotic treatment of acute UTI
lence of resistances in the prophylaxis arm. Anyhow, in
Oral 1.00 (reference)
Intravenous 0.72 (0.31 to 1.65) our study children with grade III reflux and no prophy-
Prophylaxis laxis experienced an increased number of recurrent in-
No prophylaxis 1.00 (reference) fections, although not statistically significant, whereas in
Prophylaxis 0.57 (0.26 to 1.24) the study by Garin et al,12 treatment was not just inef-
a The age has been entered in the model as continuous variable because the hazard ratio (HR) fective but even harmful. Additional specifically de-
was consistent for each month increase and categories would have been arbitrary and with no signed investigations, with a much larger population
real clinical mean. with reflux, are needed.
There were a significantly higher number of repeat
positive urine cultures in the arm with no prophylaxis
1571 in the prophylaxis arm: 10 (2.9%) and 411 (mean difference: 9.4 [95% CI: 1.5–17.3]), and this has
(71.1%), respectively, tested positive. The reported com- been the driving force behind the use of prophylactic
pliance (visual analog scale questionnaire) was good for antibiotics; however, we believe that repeat positive
86% of patients. urine cultures in absence of fever or other symptoms of
parenchymal localization of the infection are not clini-
Adverse Events cally relevant and do not produce renal scars. This is
Twenty-five (7.3%) children experienced minor adverse confirmed by the fact that the number of new scars is
effects during the 12 months of follow-up. All patients low: 1.4%. It is worth noting that this is the first study to
were on prophylaxis: 15 on co-amoxiclav and 10 on differentiate between scars as a result of repeat infections
co-trimoxazole. Adverse events were mainly vomiting or and those as a result of original pyelonephritis. The latter
gastrointestinal intolerance. were much more frequent (79 [27%] of 295). These
result from the first UTI are unrelated to prophylaxis and
DISCUSSION did not differ between the 2 study groups. Although the
Children with febrile UTIs and/or VUR are usually given risk for repeat febrile UTIs is 8.3% per year for our
prophylactic antibiotics despite there being no evidence population, concordant with a recent cohort study19 that
that this approach is protective against renal scarring or showed a 12% recurrence per year, the risk for renal
long-term medical complications.6,15 Furthermore, bac- damage from repeat infections is very low and, per se,
terial resistance to antibiotics is becoming a major issue does not justify the need for prophylaxis in our popula-
worldwide, antibiotic use being increasingly recognized tion.
as the main force producing this resistance.16,17 One Prophylaxis was associated with a higher number of
study showed that children were the main antibiotic febrile UTIs as a result of bacteria resistance. Co-trimox-
consumers, with usage rates 3 times higher than that of azole and co-amoxiclav are 2 old and frequently used
older patients, thereby increasing their exposure to the antibiotics in our area. New antibiotics, with a better
risk for bacterial resistance.18 In accordance, in our resistance profile, could have allowed a lower number of
study, the higher risk for resistance was in the prophy- recurrences in the prophylaxis arm.
laxis arm; therefore, the potential benefit of antibiotics It is worth remembering that, per protocol, all chil-
has to be weighted with the high risk for selecting resis- dren were maintained on prophylaxis until cystography
tant bacteria. (median: 40 days) from the acute infection; therefore,
According to our definition of noninferiority, this we do not have data on a complete prophylaxis-free
study showed that during a period of 12 months, no protocol, and we cannot comment on the role of antibi-
prophylaxis had no greater risk for recurrent febrile UTIs otic prophylaxis in preventing infections during this
than prophylaxis. At the study completion, 338 children early post-UTI period. The study shows that prophylaxis,
were enrolled, giving a final randomization ratio of 1:1.7 conducted for ⬃1 month for all children, can be safely
and providing 72% posthoc power compared with 70% stopped afterward. The recently published study by
as intended. The number of children who were lost to Garin et al12 seems not to have such treatment phase.
follow-up was small (7.7% at the 12-month follow-up) Anyhow, there is no comment in the article of repeated
and evenly distributed between the 2 arms of the study. UTIs during this prophylaxis-free period and whether
This fact, together with the low number of recurrent any patient was excluded by the trial because of infec-

PEDIATRICS Volume 122, Number 5, November 2008 1069

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tions before the VCUG. To have additional recommen-
dations on the role of a complete prophylaxis-free regi-
men, we need another study to compare stopping of
antibiotic immediately after treatment completion.
From the multivariate analysis, grade III reflux rep-
resents the only risk factor for the recurrence of febrile
UTIs. No prophylaxis is not a risk factor. As expected,
increasing age protects from recurrences (Table 3). It is
interesting that a recent study19 showed, in multivariable
Cox time-to-event models, that factors that were asso-
ciated with increased risk for recurrent UTI included age
3 to 5 years and higher grades (IV–V) of VUR. Prophy-
laxis was not associated with decreased risk for recurrent
UTI but was a risk factor for antimicrobial resistance.
Our study population consisted of children of both
genders, aged ⬍7 years, mostly (309 of 336) with a
documented parenchymal renal localization of the infec-
tion. A total of 128 (38%) of 336 had primary VUR
grades I to III. Exclusion criteria were urinary tract dis-
orders as a result of complex urologic malformations,
DMSA scan showing a relative function of 1 kidney
⬍30%, and VUR grades IV and V. These criteria are
routinely evaluated in clinical practice when considering
prophylaxis, meaning that the results of this study are
readily applicable.
We excluded children with grades IV to V reflux
and/or monolateral or bilateral renal hypodysplasia, be-
cause we considered those children particularly at risk
for repeat infections and renal damage. Our conclusions
do not apply to children with higher degrees of reflux.
This however opens the debate as to the need for routine
VCUG in the first place for children with normal renal
ultrasound and a first febrile UTI, who have a very low
probability to have a high-degree reflux.
CONCLUSIONS
Our study shows that prophylaxis does not reduce the
rate of febrile UTI recurrence during 12 months after the
first episode of febrile UTI in children with or without
the presence of primary nonsevere reflux. Patients with
grade III VUR seem to have significantly different results
from those with lower grades or no reflux.
ACKNOWLEDGMENTS
This study was supported by Region of Veneto (research
project 40/01) and association Il Sogno di Stefano (Ste-
phen’s Dream).
We thank all the members of Italian Renal Infection
Study Group in children (IRIS), who made the perfor-
mance of this study possible. We particularly thank
Daniela Gobber (epidemiologist), who died 2 years ago.
We also thank, Andrea Ponzoni for statistical analysis
and Manola Bettio and Pia-Sophia Wool for reviewing
the manuscript.
Data and Safety Monitoring Committee: Roberto
Buzzetti (epidemiologist), Modena; Giovanni Capasso
(pediatric nephrologist), Naples; and Roberto D’Amico
(statistician), Modena. Participants of the IRIS2 study: I.
Marella, A. Budini (Adria); L. Marcazzò, S. Bellato (Ar-
zignano); G. Audino, G. Picco (Bassano); P. Colleselli, D.
1070 MONTINI et al
Downloaded from www.pediatrics.org by on November 13, 2009
Scorrano (Belluno); L. Pavanello (Castelfranco); C. Criv-
ellaro (Chioggia); G. Cattarozzi, M. Pitter, A. Ballan (Do-
lo/Mirano); F. Rossetti, V. Cannella (Este/Monselice); G.
Svaluto-Moreolo, Caddia (Feltre); G. Pozzan, F. Maschio
(Mestre); P. Brisotto, N. Crema, S. Breseghella (Monte-
belluna); P. Luxardo, A. Toffolo (Oderzo); G. Zacchello,
G. Montini, L. Murer, C. Carasi, B. Andreetta, S. Comac-
chio, L. Rigon, S. Sartori, L. Tomasi, R. Pertile, D. Gobber
(epidemiologist), A. Ponzoni (statistician) (Padua); A.
Truini (Piove di Sacco); P.G. Flora, M. Ranieri (San
Donà); R. Dall’Amico, L. Donello (Thiene); G. Marcer, S.
Zanchetta (Soave); M. Del Majno, M. Gheno (Venice); P.
Biban, P. Fortunati (Verona-Borgo Trento); M.G. San-
tangelo, O. Gianesini (Vicenza); A. Corsini (Bentivoglio);
P.P. Molinari (Bologna); A. Zucchini (Faenza/Lugo);
Venturolli (Forlì); L. Serra (Imola); L. Casadio
(Ravenna); M. Principi (Macerata); M. Pitschiller, W.
Cassar (Bolzano); M. De Marini, G. Crescenzi (Cuneo).
Dr Montini had full access to all of the data in the
study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
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DRUGS IN PREGNANCY AND LACTATION: A REFERENCE GUIDE TO FETAL AND

NEONATAL RISK, 8TH EDITION*

Authors: Briggs, Gerald G., Freeman, Roger K., Yaffe, Sumner J.

Publisher: Lippincott Williams & Wilkins
List Price: $129.00
Reviewer: Gilad Gross, MD (Washington University School of Medicine); Jennifer
Meyer, MD (Washington University School of Medicine) contributed to this review.
DESCRIPTION: This is an all inclusive reference guide to fetal and neonatal risks
associated with drugs used during pregnancy and lactation. The book is arranged
in alphabetical order according to the drug’s American generic name. Each drug
is initially presented with a fetal risk recommendation, a breast feeding recom-
mendation, and a risk factor category (classic A through X categorization), all
contained in a color-coded box. This is followed with a descriptive fetal risk
summary, a breast-feeding risk summary, and references. The last edition of this
book was published in 2005.
PURPOSE: The purpose is to provide clinicians with the best estimate of embryo/
fetal and nursing infant risk associated with exposure to various drugs. The book
is certainly a needed reference for clinicians.
AUDIENCE: Physicians and other healthcare professionals involved in the care
of pregnant and lactating patients are the intended audience. It is appropriate for
students, residents, and physicians at all levels in various specialties, but is di-
rected predominantly at those in the fields of obstetrics/gynecology and pediatrics.
The authors are experts in the areas of pharmacology, obstetrics/gynecology, and
neonatal and developmental medicine, and have a long track record of success
with this reference.
FEATURES: This guide examines the pregnancy and breastfeeding recommen-
dations for over 1,200 drugs based on a multitude of references. Fetal risk and
breastfeeding summaries include numerous types of data including but not lim-
ited to animal data, known human data, pharmacokinetics, and metabolic phys-
iology. The introduction chapter clearly defines pregnancy and breastfeeding
recommendations as well as risk factor categories. Concluding fetal risk and
breastfeeding summaries follow the recommendations with the intent of provid-
ing clinicians with sufficient data to counsel patients on the risk/benefit ratio of a
particular drug to arrive at a decision about whether to expose the fetus or
neonate to the drug. The alphabetical organization of the book is user friendly.
The color-coded highlighted boxes with the fetal risk and breast feeding recom-
mendations as well as the risk factor category allow one to quickly reference the
conclusion of the longer explanations given in the summary sections. The size of
the book means that it is not that portable, but it comes with a code allowing
access to an online version—a highly desirable feature.
ASSESSMENT: This is a useful, high quality manual of recommendations for the
use of drugs in pregnancy and lactation. It certainly is the first book we turn to
when posed with questions about the use of certain drugs in pregnancy and
lactation. This edition covers 125 additional drugs and provides updates from the
seventh edition. This is a highly valuable reference.
*Review provided by ©Doody’s Review Service™. www.medinfonow.com

PEDIATRICS Volume 122, Number 5, November 2008 1071

Downloaded from www.pediatrics.org by on November 13, 2009
 Prophylaxis After First Febrile Urinary Tract Infection in Children? A
Multicenter, Randomized, Controlled, Noninferiority Trial
Giovanni Montini, Luca Rigon, Pietro Zucchetta, Federica Fregonese, Antonella
Toffolo, Daniela Gobber, Diego Cecchin, Luigi Pavanello, Pier Paolo Molinari,
Francesca Maschio, Sergio Zanchetta, Walburga Cassar, Luca Casadio, Carlo
Crivellaro, Paolo Fortunati, Andrea Corsini, Alessandro Calderan, Stefania
Comacchio, Lisanna Tommasi, Ian K. Hewitt, Liviana Da Dalt, Graziella Zacchello,
Roberto Dall'Amico and on behalf of the IRIS group
Pediatrics 2008;122;1064-1071
DOI: 10.1542/peds.2007-3770
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/122/5/1064
References This article cites 19 articles, 10 of which you can access for free
at:
http://www.pediatrics.org/cgi/content/full/122/5/1064#BIBL
Citations This article has been cited by 9 HighWire-hosted articles:
http://www.pediatrics.org/cgi/content/full/122/5/1064#otherartic
les
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Genitourinary Tract
http://www.pediatrics.org/cgi/collection/genitourinary_tract
Permissions & Licensing Information about reproducing this article in parts (figures,
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