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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 mL). Urine was collected with a sterile urinary bag; the
weeks to 12 months) antibiotics reduced the risk for 2 concordant consecutive urinalysis and culture were
repeat positive urine cultures (relative risk [RR]: 0.4 required to minimize the risk for false-positive tests.
[95% confidence interval (CI): 0.26 – 0.62]) compared Children also had to have at least 2 of fever ⱖ38°C,
with placebo or no prophylaxis.9–11 Only 1 study re- raised inflammatory indices in the first 48 hours (eryth-
ported an increased risk (RR: 1.93 [95% CI: 0.63–5.92]) rocyte sedimentation rate ⱖ30 mm in the first hour or
of recurrence of symptomatic UTI in 27 children who C-reactive protein ⱖ3 times upper limit of normal val-
received prophylaxis versus 32 children who received ues, or both), and neutrophil count above the normal
placebo.9 In these 3 trials, the study population (mainly values for age.
girls and few patients with urinary tract abnormalities)
was small and did not reflect the pediatric population to Imaging Studies
whom prophylaxis is usually given. Bacterial resistance
was not considered. Prerandomization
In 1 randomized study,12 the role of prophylaxis in Ultrasonography and DMSA renal scans were performed
reducing the frequency of UTIs among patients with within 10 days from commencement of antibiotic for the
acute pyelonephritis was not supported. This trial febrile UTI. Focal or diffuse areas of decreased uptake in
showed that the use of antibiotic prophylaxis was not the first DMSA scan, without evidence of cortical loss,
only ineffective but also harmful: among children with were considered indicative of acute pyelonephritis.
vesicoureteral reflux (VUR), recurrent acute UTIs was Voiding cystourethrography (VCUG; radiology, with 1
observed for 7 of 55 patients who received urinary an- filling) was performed within 2 months of UTI.
tibiotic prophylaxis, compared with only 1 of the 58
patients with no prophylaxis (P ⫽ .0291). In all of the 7 Postrandomization
cases, the offending bacteria showed resistance to the Repeat DMSA scans were planned 12 months from ran-
antibiotic used for prophylaxis. In this study, the anti- domization, or, when a new episode of febrile UTI oc-
microbial treatment of the acute episode was not stan- curred, at least 6 months after infection. Renal scarring
dardized, intention-to-treat (ITT) analysis was not per- was defined as decreased uptake with distortion of the
formed, and the age range was extremely wide. We contours or as cortical thinning with loss of parenchymal
conducted a noninferiority, randomized, controlled trial volume. Two nuclear physicians, who were blinded to
to determine whether no prophylaxis for children who the patients’ test results, interpreted the scans indepen-
were aged 2 months to 7 years and had a first febrile UTI, dently. Discrepancies were resolved by discussion between
with or without the presence of primary nonsevere VUR, the assessors.
is similar to antimicrobial prophylaxis for 12 months in
producing the recurrence of febrile UTIs. Antibiotic Treatment of Febrile UTI
Antibiotic treatment of the initial UTI was either intra-
venous ceftriaxone for 3 days followed by oral co-amoxi-
METHODS clav for 7 days or oral treatment only with co-amoxiclav
The study is a controlled, randomized, multicenter, for 10 days. After completion of treatment, all children
open-labeled, parallel-group trial. It was originally de- were given prophylaxis until the VCUG was performed.
signed as a 3-arm trial subsequently amended to be a
2-arm noninferiority study. It was conducted from May
Randomization
2000 to August 2006 at 22 pediatric units located in
The randomization scheme was computer-generated by
Northeast Italy, coordinated by the Unit of Nephrology,
the coordinating center. Randomization, 1:1:1 for the 3
Dialysis and Transplantation of the Pediatric Department
arms, was stratified by center, gender, and clinical group
of Padova. The ethics committee of each participating
on the basis of presence or absence of VUR and of the
center approved the protocol. The parents of each child
parenchymal localization of the acute UTI. There were 3
signed an informed consent before participation.
groups: (1) acute positive DMSA without VUR, (2) acute
negative DMSA with VUR, and (3) acute positive DMSA
Patient Inclusion and Exclusion Criteria with VUR. Each participating center received 6 series
The study population was recruited among children who with allocation codes. The series were 1 for each stra-
had a first episode of febrile UTI, with or without pri- tum, and each series contained 12 sealed, opaque enve-
mary nonsevere VUR (first to third degree). Recruitment lopes. Every envelope was numbered with a sequential
was confined to children who were aged 2 months to 7 number. Each participating center assigned every en-
years and had normal renal function.13 Exclusion criteria rolled child to a stratum (on the basis of gender and
were complex urologic malformations and/or severe re- clinical group). The allocation code for that child was
nal damage (dimercaptosuccinic acid [DMSA] scintigra- then assigned, opening the next envelope in that stra-
phy showing a relative function of 1 kidney ⬍30%). tum series.
The diagnosis of first febrile UTI at presentation was In the second part of the study, the 1:1 randomization
made by fever ⱖ38°C, pyuria (2 concordant consecutive scheme was automatically generated, stratified as before,
test results with white cell counts ⱖ25/␮L), and urine and kept centrally. After assigning the child to a stratum,
culture (2 concordant consecutive tests with growth of the centers received the allocation treatment from the
only 1 microorganism ⱖ100 000 colony-forming units/ coordinating center. Investigator meetings to standard-

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ize good clinical practice were organized before and dur- of .05 (1-sided), maintaining the assumption of 20%
ing the study. incidence of recurrence, and considering an upper con-
fidence limit of 30% for noninferiority for the no-pro-
Study Interventions phylaxis arm. The patients who were enrolled after the
Recruited patients were allocated to group A, no pro- amendment were randomly assigned in a 1:1 ratio be-
phylaxis, or group B, prophylaxis (co-trimoxazole or tween no prophylaxis and prophylaxis, with a final ex-
co-amoxiclav both at the dosage of 15 mg/kg per day). pected ratio of 1:1.5.
Outpatient urine cultures were performed monthly for
the first 6 months and then every 2 months; outpatient Statistical Analysis
clinic visits were at 6 and 12 months. A DMSA scheduled In the ITT analysis, 2 scenarios were considered for
at 12 months ended follow-up for all patients. Children patients who exited the trial (lost to follow-up): (1) all
who experienced 2 recurrent febrile UTIs were switched “failures” and (2) all “successes.” The efficacy compari-
to prophylaxis when allocated to no prophylaxis and to son between “prophylaxis” and “no prophylaxis” was
other antibiotic or referred for VUR surgery when al- performed considering the differences between treat-
ready allocated to prophylaxis. Data collected were ments and the 95% CI for this difference. The binomial
symptoms and signs of UTI (urinalysis, urine culture), outcome measures were tested using the ␹2 test (Fisher
compliance to treatment and adverse effects, and resis- test and Pearson test); the numerical outcome measures
tance to the prophylactic antibiotic in case of positive were tested using Student’s t test or the Mann-Whitney
urine cultures. Compliance was evaluated by assessment test, as appropriate. A multivariate survival analysis was
of antimicrobial activity in urine at the routine urine conducted using the Cox proportional hazards model.
cultures and by a questionnaire with a visual analogic The survival analyses conducted using the Cox propor-
scale of parents’ assessment of “difficulty” in following tional hazards model have been integrated with the
treatment. 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
Outcome Measurements calculated as previously suggested.14
The primary end point was the first recurrence of febrile The software Stata 9.0 (Stata Corp, College Station,
UTIs in the 12 months after randomization. Recurrent TX) was used for the statistical analysis. A secondary
UTI was defined by presence of fever (⬎38°C), pyuria, analysis comparing the effectiveness of the prophylactic
and urine culture as defined in the inclusion criteria. treatment in subgroups of patients defined by age, gen-
Additional recurrences and arm switches were therefore der, and grade of reflux was performed.
not accounted as “failure” per se.
Secondary end point was the rate of new renal scar- RESULTS
ring defined as scarring, other than at the site of the Between July 2000 and September 2005, 22 centers
initial pyelonephritis, after 12 months. Exploratory anal- enrolled and randomly assigned 338 patients: 127
yses were also performed to evaluate the risk for repeat (37.6%) to no prophylaxis and 211 (62.4%) to pro-
positive urine cultures and the rate of scarring at the site phylaxis (113 [54%] co-amoxiclav and 98 [46%] co-
of the initial infection as potential end points. trimoxazole). The final randomization ratio was 1:1.7
(expected 1:1.5). Follow-up was completed in August
Study Design and Sample Size 2006. Three patients were wrongly enrolled (2 did not
The study was designed as a controlled, randomized, complete the screening work out; 1 older than 7
open-label, 3-armed, parallel-group study, comparing years). Adherence to the protocol was good: 26 pa-
no prophylaxis, prophylaxis with co-trimoxazole, and tients who were lost to follow-up were evenly distrib-
prophylaxis with co-amoxiclav. A first comparison was uted in the 2 arms (10 [7.9%] of 127 and 16 [7.6%] of
planned between no prophylaxis and prophylaxis, with 211). Patient allocation and compliance to protocol
a subsequent comparison between the 2 antibiotics if the are shown in Fig 1.
pooling of prophylaxis had shown a better outcome. The acute infection was treated with initial intrave-
The study aimed to enroll 660 patients in a 1:1:1 ratio nous antibiotics for 151 (45%) patients and with com-
across the 3 groups. Enrollment was slower than antic- plete oral treatment for 183 (55%), unknown in 4. The
ipated, reaching 237 patients by August 2003 (evenly distribution of oral and intravenous treatment was sim-
allocated to no prophylaxis, co-trimoxazole, and co- ilar in the 2 arms (P ⫽ .22). All children were given a
amoxiclav). Thus, following the recommendation of the prophylactic regimen of co-amoxiclav until VCUG was
Data and Safety Monitoring Committee to take action to performed for a median (interquartile range [IQR]) pe-
be able to complete enrollment in a reasonable time riod of 40 days (33–50); no prophylaxis: 40 (32–51);
frame, we decided to modify the study design, maintain- prophylaxis: 41 (34 –50). Baseline characteristics were
ing the primary objective (comparison between prophy- similar for children who were randomly assigned in the
laxis and no prophylaxis) and abandoning the compar- 2 arms (Table 1).
ison between the 2 antibiotics regimens.
The new sample size for the 2-arm, noninferiority Primary Outcome
trial was calculated to be 313 patients (rounded to 340, Febrile UTIs were not significantly different between
for possible dropouts), setting power at 70% and ␣ error the 2 groups during follow-up: 12 (9.45%) of 127 in the

1066 MONTINI et al
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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- ered in bivariate analysis: younger age and VUR grade
ference: 2.34% [95% CI: 3.8%– 8.4%]; Table 2). These were associated with recurrence of febrile UTI. The mean
results hold true even once patients are stratified by age was 7.1 vs 14.6 months for children with recurrence
grade of VUR (Table 2). These data were obtained with versus no recurrence (P ⫽ .02). The rate of recurrences
ITT analysis, considering the patients lost to follow-up increased with the grade of VUR, from 8 (3.8%) of 210
before the 12-month visit as having no recurrence. Data for patients with no VUR to 2 (6.7%) of 30, 5 (8.6%) of
are shown also as a Kaplan-Meier for time free of events 58, and 12 (30%) of 40 for patients with VUR grades I,
in Fig 2. Median time (IQR) to febrile recurrences was II, and III, respectively (P ⬍ .01). In the Cox proportional
113 days (57–192) with no significant difference be- hazards model, no prophylaxis was not a risk factor for
tween the 2 groups (log-rank test P ⫽ .36). We found recurrence of febrile UTIs; older age was confirmed to be
similar results when we counted all patients who were protective and grade III reflux to be a risk factor (Table
lost to follow-up as having a recurrence during the 12 3). The number of patients to be treated to prevent a
months and with an on-treatment analysis (Table 2). febrile recurrence was 41.7 children for 1 year.
The exploratory analysis showed that the rate of repeat
positive urine culture and concomitant positive urinaly- Secondary Outcomes
sis was significantly different between the 2 groups: 24 A total of 87% (295) of enrolled patients had the DMSA
(18.9%) of 127 on no prophylaxis and 20 (9.5%) of 211 scan at 1 year with a median (IQR) time to DMSA of 351
on prophylaxis (P ⫽ .02). days (329 –385) after enrollment. A new renal scar (in a
Age, gender, VUR grade, treatment of the initial UTI different site from the initial pyelonephritis) was found
(oral versus intravenous), and prophylaxis were consid- in 4 (1.4%) of 295 patients (Table 2); the new scars

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

1068 MONTINI et al
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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


Downloaded from www.pediatrics.org by on November 13, 2009
tions before the VCUG. To have additional recommen- Scorrano (Belluno); L. Pavanello (Castelfranco); C. Criv-
dations on the role of a complete prophylaxis-free regi- ellaro (Chioggia); G. Cattarozzi, M. Pitter, A. Ballan (Do-
men, we need another study to compare stopping of lo/Mirano); F. Rossetti, V. Cannella (Este/Monselice); G.
antibiotic immediately after treatment completion. Svaluto-Moreolo, Caddia (Feltre); G. Pozzan, F. Maschio
From the multivariate analysis, grade III reflux rep- (Mestre); P. Brisotto, N. Crema, S. Breseghella (Monte-
resents the only risk factor for the recurrence of febrile belluna); P. Luxardo, A. Toffolo (Oderzo); G. Zacchello,
UTIs. No prophylaxis is not a risk factor. As expected, G. Montini, L. Murer, C. Carasi, B. Andreetta, S. Comac-
increasing age protects from recurrences (Table 3). It is chio, L. Rigon, S. Sartori, L. Tomasi, R. Pertile, D. Gobber
interesting that a recent study19 showed, in multivariable (epidemiologist), A. Ponzoni (statistician) (Padua); A.
Cox time-to-event models, that factors that were asso- Truini (Piove di Sacco); P.G. Flora, M. Ranieri (San
ciated with increased risk for recurrent UTI included age Donà); R. Dall’Amico, L. Donello (Thiene); G. Marcer, S.
3 to 5 years and higher grades (IV–V) of VUR. Prophy- Zanchetta (Soave); M. Del Majno, M. Gheno (Venice); P.
laxis was not associated with decreased risk for recurrent Biban, P. Fortunati (Verona-Borgo Trento); M.G. San-
UTI but was a risk factor for antimicrobial resistance. tangelo, O. Gianesini (Vicenza); A. Corsini (Bentivoglio);
Our study population consisted of children of both P.P. Molinari (Bologna); A. Zucchini (Faenza/Lugo);
genders, aged ⬍7 years, mostly (309 of 336) with a Venturolli (Forlì); L. Serra (Imola); L. Casadio
documented parenchymal renal localization of the infec- (Ravenna); M. Principi (Macerata); M. Pitschiller, W.
tion. A total of 128 (38%) of 336 had primary VUR Cassar (Bolzano); M. De Marini, G. Crescenzi (Cuneo).
grades I to III. Exclusion criteria were urinary tract dis- Dr Montini had full access to all of the data in the
orders as a result of complex urologic malformations, study and takes responsibility for the integrity of the data
DMSA scan showing a relative function of 1 kidney and the accuracy of the data analysis.
⬍30%, and VUR grades IV and V. These criteria are
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for pyelonephritis in children: multicentre randomised con-
and/or monolateral or bilateral renal hypodysplasia, be- trolled non-inferiority trial. BMJ. 2007;335(7616):386
cause we considered those children particularly at risk 3. Jahnukainen T, Chen M, Celsi G. Mechanisms of renal damage
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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


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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
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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
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