Prospective, Randomized Trial Comparing Short and Long Intravenous

Antibiotic Treatment of Acute Pyelonephritis in Children: Dimercaptosuccinic

Acid Scintigraphic Evaluation at 9 Months
François Bouissou, Caroline Munzer, Stéphane Decramer, Bernard Roussel, Robert
Novo, Denis Morin, Marie Pierre Lavocat, Claude Guyot, Sophie Taque, Michel
Fischbach, Eric Ouhayoun, on behalf of the French Society of Nuclear Medicine and
Molecular Imaging, Chantal Loirat and on behalf of the French Society of Pediatric
Nephrology
Pediatrics published online Feb 11, 2008;
DOI: 10.1542/peds.2006-3632

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/peds.2006-3632v1

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ARTICLE

Prospective, Randomized Trial Comparing Short and

Long Intravenous Antibiotic Treatment of Acute
Pyelonephritis in Children: Dimercaptosuccinic Acid
Scintigraphic Evaluation at 9 Months
François Bouissou, MDa, Caroline Munzer, PhDa, Stéphane Decramer, MDa, Bernard Roussel, MDb, Robert Novo, MDc, Denis Morin, MDd,
Marie Pierre Lavocat, MDe, Claude Guyot, MDf, Sophie Taque, MDg, Michel Fischbach, MDh, Eric Ouhayoun, MDi, on behalf of the
French Society of Nuclear Medicine and Molecular Imaging, Chantal Loirat, MDj, on behalf of the French Society of Pediatric Nephrology

aNéphrologie Pédiatrique, Hôpital des Enfants, Université Paul Sabathier, Centre Hospitalier Universitaire Purpan, Toulouse, France; bNéphrologie Pédiatrique, American

Memorial Hospital, Centre Hospitalier Universitaire Reims, Beims, France; cNéphrologie Pédiatrique, Hôpital Jeanne de Flandre, Université Lille 2, Centre Hospitalier
Régional Universitaire Lille, Lille, France; dNéphrologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université Montpellier I, Centre Hospitalier Universitaire Montpellier,
Montpellier, France; eNéphrologie Pédiatrique, Centre Hospitalier Universitaire Saint Etienne, Saint Etienne, France; fNéphrologie Pédiatrique, Hôpital Mère Enfant,
Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France; gNéphrologie Pédiatrique, Centre Hospitalier Universitaire Rennes, Rennes, France;
hNéphrologie Pédiatrique, Hôpital Hautepierre, Université Louis Pasteur, Centre Hospitalier Universitaire Strasbourg, Strasbourg, France; iMédecine Nucléaire, Université

Paul Sabathier, Centre Hospitalier Universitaire Purpan Toulouse, Toulouse, France; jService de Néphrologie, Faculté de Médecine Denis Diderot, Université Paris VII,
Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. We report a prospective, randomized, multicenter trial that compared the
effect of 3 vs 8 days of intravenous ceftriaxone treatment on the incidence of renal
scarring at 6 to 9 months of follow-up in 383 children with a first episode of acute www.pediatrics.org/cgi/doi/10.1542/
peds.2006-3632
pyelonephritis.
doi:10.1542/peds.2006-3632
METHODS. After initial treatment with intravenous netilmicin and ceftriaxone, patients Key Words
were randomly assigned to either 5 days of oral antibiotics (short intravenous children, acute pyelonephritis, antibiotics,
treatment) or 5 days of intravenous ceftriaxone (long intravenous treatment). In- DMSA scintigraphy
clusion criteria were age 3 months to 16 years and first acute pyelonephritis episode, Abbreviations
defined by fever of ⬎38.5°C, C-reactive protein level of ⬎20 mg/L, and bacteriuria at APN—acute pyelonephritis
DMSA— dimercaptosuccinic acid
⬎105/mL. All patients underwent 99m technetium-dimercaptosuccinic acid scintig- VUR—vesicoureteral reflux
raphy 6 to 9 months after inclusion. A total of 548 children were included, 48 of CRP—C-reactive protein
99mTc—99m technetium
whom were secondarily excluded and 117 of whom were lost to follow-up or had
OR— odds ratio
incomplete data; therefore, 383 children were eligible, 205 of them in the short
Accepted for publication Aug 1, 2007
intravenous treatment group and 178 in the long intravenous treatment group.
Address correspondence to François Bouissou,
RESULTS. At inclusion, median age was 15 months, median duration of fever was 43 MD, Néphrologie Pédiatrique, Hôpital des
Enfants, TSA70034, Avenue de Grande
hours, and median C-reactive protein level was 122 mg/L. A total of 37% (143 of Bretagne, 31059 Toulouse Cedex 6, France.
383) of patients had a vesicoureteral reflux grades 1 to 3. Patient characteristics at E-mail: bouissou.f@chu-toulouse.fr
inclusion were similar in both groups, except for a significantly higher proportion of PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
girls in the short intravenous treatment group. The frequency of renal scars at American Academy of Pediatrics
scintigraphy was similar in both groups. Multivariate analysis demonstrated that
renal scars were significantly associated with increased renal height at initial ultra-
sound and with the presence of grade 3 vesicoureteric reflux.
CONCLUSIONS. The incidence of renal scars was similar in patients who received 3 days compared 8 days of intravenous
ceftriaxone. Increased renal height at initial ultrasound examination and grade 3 vesicoureteric reflux were signif-
icant risk factors for renal scars.

A CUTE PYELONEPHRITIS (APN) is common in children and infants, with an estimated incidence of 1.28 per 1000 in girls
and 0.18 per 1000 in boys younger than 14 years and a prevalence in febrile infants of 5.3%.1–3 APN can induce
irreversible renal scars, with a risk for hypertension or chronic renal failure at long-term follow-up.4–7 With the use of

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dimercaptosuccinic acid (DMSA) scans, currently the best
way to detect renal scars,8–10 the percentage of residual
renal scars after 1 APN episode has been shown to vary
between 25% and 60%.11,12 This variability is attributable
to the heterogeneity of the populations studied and the
difficulty in differentiating APN-induced scars from con-
genital renal dysplasia associated with urinary tract abnor-
malities. The prevention of renal scars by early and appro-
priate antibiotics is essential. The choice of the antibiotics
depends of the bacterial ecology and may vary from 1
country to another.13,14 Monotherapy or bitherapy can be
used. Whether the duration and the way of administration
of antibiotics influence the risk for renal scars is debated.
Furthermore, general practice was shown to differ widely
from 1 pediatric team to another.15–18 Only a limited num-
ber of prospective, randomized studies have been report-
ed.19 In 1999, the study by Hoberman et al20 found no
significant differences in persistent renal damage at 6
months between oral cefotaxime therapy (14 days) and
intravenous therapy (3 days) followed by oral therapy (10
days). Three other trials found no significant differences in
persistent renal damage between intravenous therapy (3– 4
days) followed by oral therapy and intravenous therapy for
7 to 14 days.21–23 Concerns persist about the percentage of
residual scars, and trials still are required to confirm that
oral cefixime or short courses of intravenous therapy fol-
lowed by oral therapy are sufficient to limit the risk for
renal damage and to determine the optimal total duration
of therapy.20
We report a prospective, randomized, multicenter (17
centers) trial, comparing short and long intravenous an-
tibiotic treatment in children with a first episode of APN.
Total antibiotic duration was 8 days in both groups.
Initial treatment was intravenous administration of
netilmicin (7 mg/kg for 2 days) and ceftriaxone (50
mg/kg for 3 days), followed either by 5 days of intrave-
nous ceftriaxone in long treatment group or by 5 days of
oral antibiotic in short treatment group. The end point
was to compare the frequency of renal scars on DMSA
scan 6 to 9 months later. Considering the difficulty in
differentiating acquired or congenital scars, we excluded
patients with known uropathy, obstructive uropathy or
vesicoureteral reflux (VUR) grades 4 and 5.
METHODS
Patient Selection
Inclusion criteria were age between 3 months and 16
year; first acute episode of APN, defined by fever of
⬎38.5°C, C-reactive protein (CRP) level of ⬎20 mg/L,
positive dipstick test (nitrite and leukocytes), monomi-
crobial positive urine culture results at ⬎100 000 colo-
ny-forming units/mL, with Escherichia coli, Proteus mira-
bilis, or Klebsiella species; and no renal hypoplasia/
dysplasia at ultrasound examination.
Exclusion criteria were age of ⬍3 months or ⬎16
years; known patients followed for any kind of uropa-
thy; previous urinary tract infection; new patients with
obstructive uropathy (pelvis dilation ⬎10 mm) or renal
hypoplasia/dysplasia (kidney height ⬍2 SD) at initial
ultrasound examination; urine culture positive for
e554 BOUISSOU et al
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Pseudomonas aeruginosa, Staphylococcus, or group D Strep-
tococcus; fever of ⬎38.5°C for ⬎4 days at admission; or
concomitant nonurinary infection. Patients who were
judged by the physician to be severally ill were excluded
from randomization. Secondary exclusion criteria were
high-grade VUR (more than grade 3), detected at cys-
tography, or APN recurrence during the period until
DMSA scintigraphy.
All eligible patients were included and randomly as-
signed after informed consent was obtained from parents
and children when old enough.
Treatments
Total duration of antibiotic treatment was 8 days in both
groups. Initial intravenous antibiotic treatment was in-
travenous netilmicin (7 mg/kg) for 2 days and ceftriax-
one (50 mg/kg) for 3 days, in both groups. According to
randomization, patients subsequently received either 5
days of oral antibiotic according to the organism’s sen-
sitivity (short treatment group) or 5 days of intravenous
ceftriaxone (long treatment group). All patients subse-
quently received a prophylactic trimethoprim-sulfame-
thoxazole treatment until cystography.
Investigations
At admission, a urine specimen was collected in a sterile
bag in young children or by midstream catch in older
children for dipstick for leukocyte esterase and nitrite,
white blood cell count, Gram stain, and urine culture.
Blood sample was collected for blood cell count, serum
creatinine and CRP levels, and blood culture). Renal and
urinary tract ultrasound examination with renal height
measurement was performed before randomization. We
considered a kidney to be enlarged when the kidney
height was ⬎1.5 cm above normal for age.
At 15 to 30 days, all patients underwent a voiding
cystography (results: no reflux or reflux graded accord-
ing to the international classification, grade 1–5).
Between 6 and 9 months (median: 8.35), a 99m
technetium (99mTc)-DMSA scintigraphy was performed
according to the protocol of Mackenzie24: intravenous
99mTc-DMSA dosage was adapted to weight (European
Task Force recommendations25), and acquisition was
performed 2 to 4 hours later, at 4 angles of incidence
(anterior, posterior, oblique right, and oblique left) with
256 ⫻ 256 matrix during 5 minutes. In the youngest
patients, a pinhole was used and acquisition time was
prolonged 10 minutes. All biophysical centers were re-
quired to test the quality of DMSA radiopharmaceutical
and to control the ␥ camera according to the recommen-
dations of the French Society of Biophysics and Nuclear
Medicine. The relative percentage of DMSA fixation of
each kidney was calculated, and all pictures were sent to
the coordination center for qualitative interpretation.
The defects of DMSA fixation were evaluated according
to criteria of Patel et al.26 Cortical defect or heteroge-
neous parenchymal uptake, with or without renal shape
modification, was considered as scar. During the follow-
up, urinalysis was required in case of intercurrent fever.
 Assessed for eligibility: 802
(first APN episode,
no known uropathy,
no obstructive uropathy or renal
hypoplasia on initial ultrasound)

Enrollment
Parental refusal:
January 99–June 2002
254

Randomly
assigned: 548

Short IV: 277 Long IV: 271

Secondary exclusion:
22 Secondary
exclusion: 26
APN recurrence: 15
APN recurrence: 17
Severe uropathy: 7
(VUR grade 4 or 5 ) Severe uropathy: 9
(VUR grade 4 or 5 )

Incomplete Incomplete
data: 50 data: 67

Lost to follow-up: Lost to follow-up:

37 50

DMSA refusal: DMSA refusal:

13 17

Analyzed: 205 Analyzed: 178

FIGURE 1
Consort diagram.

Running Protocol were registered in a computer base according to the

The inclusion period was from January 1999 to June
2002, and follow-up ended in June 2003. The random-
ization (random tables) was centralized and stratified by
center, by blocks of 20 numbered sealed opaque enve-
lopes with equal numbers of treatment assignments.
Allocation was done by the local investigator by opening
a numbered sealed envelope 48 hours after admission
and after informed consent by the parents.
All recorded data were completed by a local investi-
gator and were sent to the coordination center. Data
french legislation (Commission nationale de l’infor-
matique et des libertés), on Epi Info software (Centers
for Disease Control and Prevention, Atlanta, GA). All
DMSA scans were reviewed (quality of the scan, size,
shape, cortical or medullar defect, localization, num-
ber of defects, unilateral or bilateral) in December
2003 by a group of 4 independent biophysicians, with-
out knowledge of treatment group. In case of disagree-
ment, DMSA scans were reanalyzed in a common
session.

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 TABLE 1 Patient Characteristics at Inclusion
Characteristic Total Short Treatment Long Treatment
Population Group Group
No. of patients 383 205 178
No. of patients per center
Mean 23 12 11
Median (range) 27 (2–58) 14 (1–29) 13 (1–29)
Boys, n (%) 86 (22) 33 (16) 53 (30)
Girls, n (%) 297 (78) 172 (84)a 125 (70)
Age, mo
Mean 34 37 31
Median (range) 15 (3–191) 17 (3–191) 13 (3–171)
Fever duration before therapy, h
Mean 46 44 48
Median (range) 43 (0–162) 38 (0–162) 45 (0–146)
Highest body temperature, °C
Mean 39.7 39.7 39.8
Median (range) 40.0 (38.1–41.7) 40.0 (38.1–41.0) 40.0 (38.5–41.7)
CRP, mg/L
Mean 122 117 128
Median (range) 100 (20–890) 101 (21–739) 100 (20–890)
aP ⫽ .001.

Statistical Analysis APN in 32, grade 4 or 5 VUR in 16). The proportion of

The sample size was calculated to demonstrate a differ-
ence of 10% in the percentage of renal scars between the
2 groups (␣ risk: 5%; power: 80%; 2-sided hypothesis
test). The size needed was 493 patients. All analyses
were performed by using Epi Info and Stata (Stata Corp,
College Station, TX) software in intention to treat.
Odds ratios (ORs) and 95% confidence intervals were
estimated by using unconditional logistic regression
models. Adjustment for potential confounding factors
such as gender and age and mutual adjustments were
tested.27–31
RESULTS
Demographic and Population Characteristics
During the enrollment period, 802 children were eligible,
548 of whom were included and allocated to 1 of the 2
groups after randomization; 165 of these 548 patients were
not analyzed: 117 because of incomplete data (nonatten-
dance at last visit in 87, parental refusal of DMSA scan in
30) and 48 because of secondary exclusion (recurrence of
nonanalyzed patients was comparable in the 2 groups
(short treatment group: 26% [72 of 277]; long treatment
group: 34% [93 of 271]; P ⫽ .12). Finally, 383 patients
were analyzed at the end of the study: 205 in the short
treatment group and 178 in the long treatment group (Fig
1). Patient characteristics were comparable between the 2
groups, except for a higher proportion of girls in short
treatment group (Tables 1 and 2). Gender was similarly
distributed in analyzed and nonanalyzed patients (data not
shown). The duration of fever before therapy was longer in
the long treatment group, but this did not reach signifi-
cance (P ⫽ .19). Urine culture was positive for Escherichia
coli in 97% (200 of 205) of patients in the short treatment
group and 96% (172 of 178) in the long treatment group
(not significant). In the short treatment group, the oral
antibiotic after the 3-day intravenous course was cefixime
in 127, amoxicillin-clavulanic acid in 41, and tri-
methoprim-sulfamethoxazole in 37. The initial ultra-
sound examination showed comparable abnormalities
in both groups. The proportion of patients with VUR

TABLE 2 Initial Radiologic Findings

Finding Total Population Short Treatment Long Treatment
(N ⫽ 383) Group (n ⫽ 205) Group (n ⫽ 178)
Ultrasound examination
Kidney height, cm
Mean 7.1 7.0 7.1
Median (range) 7.0 (5–12) 7.0 (5.0–12.0) 7.0 (5.0–11.0)
Ultrasound signs of APN, n (%) 77 (20) 36 (18) 41 (23)
Focal 58 30 28
Edema 24 10 14
VUR at cystography, n (%) 143 (37) 73 (36) 70 (39)
Grade 1 32 16 16
Grade 2 86 44 42
Grade 3 25 13 12
No statistically significant differences were found between the 2 groups.

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 TABLE 3 Results of 99mTc-DMSA Scintigraphy
Parameter Total Population Short Treatment Long Treatment OR (95% CI)
(N ⫽ 383) Group (n ⫽ 205) Group (n ⫽ 178)
Scars, n (%) 57 (15) 26 (13) 31 (17) 1.45 (0.79–2.67)
Focal cortical defects, n (%) 25 (7)a 12 (5.8) 11 (6.1) 1.27 (0.53–3.06)
Upper pole, n 14 7 7
Median , n 0 0 0
Lower pole, n 9 5 4
Heterogeneous parenchymal 21 (5.5)a 10 (4.8) 11 (6.1) 1.28 (0.49–3.36)
defects, n (%)
Upper pole, n 13 6 7
Median, n 4 1 3
Lower pole, n 11 6 5
Kidney shape deformation, n (%) 24 (6)a 11 (5.3) 13 (7.3) 1.39 (0.57–3.43)
Upper pole, n 15 7 10
Median, n 5 4 2
Lower pole, n 14 0 1
CI indicates confidence interval.
a Some patients had both cortical defects and shape deformation.

was also similar (Table 2). All population characteris-
tics were similar in analyzed and nonanalyzed patients
(data not shown). DMSA scintigraphs showed renal
scars in 15% of patients (57 of 383), most often focal
(Table 3).
ent hypothesis and confirmed that long (8 days) intra-
venous treatment with ceftriaxone did not seem to
reduce the risk for renal scars compared with short (3
days) intravenous treatment. Analysis in secondarily ex-
cluded patients gave similar results (data not shown).

Comparison Between the 2 Treatment Groups
The presence of scars was slightly higher in the long
treatment group than in the short treatment group (17%
vs 13%), but the difference was not statistically signifi-
cant (Table 3). Sensitivity analyses were done on differ-
Risk Factors for Renal Scars
The correlations between the presence of scars and dif-
ferent variables of interest are indicated in Table 4. Bi-
variate analysis indicated that scars were significantly
more frequent in patients with VUR grades 2 and 3, in

TABLE 4 Risk Factors of Renal Scars, Bivariate Analysis

Risk Factor Renal Scars No Scars OR 95% CI P
(N ⫽ 57), n (%) (N ⫽ 326), n (%)
Age, mo
⬍18 28 (49) 191 (59) 1.47 0.80–2.69 .180
⬎18 29 (51) 135 (41)
Boys 11 (19) 75 (23) 1.25 0.59–2.72 .530
Girls 46 (81) 251 (77)
Delay of antibiotic therapy, d
⬍2 27 (47) 178 (55) 1.34 0.73–2.45 .310
ⱖ2 30 (53) 148 (45)
Fever duration, d
⬍3 20 (35) 146 (45) 1.50 0.80–2.83 .170
ⱖ3 37 (65) 180 (55)
CRP, mg/L
⬍100 21 (37) 169 (52) 1.85 1.00–3.45 .030
ⱖ100 36 (63) 157 (48)
VUR
No 26 (46) 214 (65) 1.0 Reference
Yes 31 (54) 112 (34) 2.28 1.24–4.21 .004
Grade
1 5 (9) 27 (8) 1.52 0.54–4.28 .430
2 17 (30) 69 (21) 2.02 1.03–3.94 .040
3 9 (16) 16 (5) 4.60 1.85–11.48 .001, ⬍.010a
Initial kidney height
Normal 52 (91) 316 (97)
Enlargedb 5 (9) 10 (3) 3.04 0.86–10.29 .050
a For
trend.
b More than 1.5 cm over normal height for age.

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 TABLE 5 Risk Factors of Renal Scars: Multivariate Analysis
Parameter OR 95% CI
VUR grade
0 Reference — —
1 1.42 0.50–4.03
2 1.72 0.87–3.40
3 4.61 1.84–11.57
Enlarged kidney on initial ultrasound 3.19 1.00–10.16
CRP ⱖ 100 mg/L 1.71 0.94–3.08
a For trend.
patients with CRP levels of ⱖ100 mg/L, and when initial
ultrasound showed enlarged kidney(s). The presence of
scars was independent of age, gender, delay of antibiotic
treatment, and total fever duration.
Multivariate analysis (Table 5) confirmed that the
incidence of scars was significantly correlated with the
presence of VUR. The risk significantly increased with
the grade (grade 1 OR: 1.42; grade 2 OR: 1.72; grade 3
OR: 4.61; P ⫽ .002 for trend). Enlarged kidney at initial
ultrasound examination was also significantly correlated
to the risk for scars (OR: 3.19). Adjustment for potential
confounding factors such as gender and age did not
change the results. Estimations remained unchanged af-
ter mutual adjustments for the different variables of
interest, although CRP levels of ⱖ100 mg/L no longer
appeared as a risk factor for scars (Table 2).
DISCUSSION
Only 4 randomized studies that compared the incidence
of renal scars as demonstrated by DMSA scintigraphy
according to antibiotic treatment modalities in children
with APN have been published.20–23 Our study is the
largest prospective trial performed in children with APN.
The multicenter setup of this study allowed the inclusion
of a large number of children without severe uropathy at
the first episode of APN. We showed that the incidence
of permanent renal damage is similar in children who
received 8 days intravenous treatment and in those who
received 3 days intravenous treatment followed by 5
days of oral antibiotic; however, several points of our
study need to be discussed.
First because of the number of incomplete data and
secondary exclusion, this study did not have sufficient
power to detect a superiority of 1 treatment modality
P over the other. Nevertheless, sensitivity analysis showed
that if 1 treatment was better than the other, then it
would be the short treatment.
.510 Second, the bacteriologic test was done on urine that
.120 was collected with sterile bags for young children, with
.001, ⬍.002a an increased risk for false-positive bacteriuria. However,
.049 this risk was equally distributed between the 2 groups,
.075 and positive results with several types of colonies at
urine culture were discarded.
Third, our 2 study groups were similar except for a
significantly higher proportion of boys in the long intra-
venous treatment group, but age, degree and duration of
fever before treatment initiation, CRP, proportion of
children with VUR, and VUR grades were nonsignifi-
cantly different between the 2 groups. In addition, esti-
mations remained unchanged in multivariate analyses
that included gender.
For minimization of the patients’ irradiation burden
and the cost of the study, the inclusion criteria were only
clinical and bacteriologic. We chose to perform only a
late DMSA scintigraphy to detect residual scars; there-
fore, patients with no initial parenchymal lesions of APN
were most probably included. Nevertheless, the propor-
tion of patients with febrile urinary tract infection with-
out APN as demonstrated by DMSA scintigraphy is
known to be ⬃30%20,21,23 and must have been equally
distributed between the 2 groups.
Here we showed that the incidence of permanent
renal damage in children after a first episode of APN was
similar after 3 days or 8 days of intravenous administra-
tion of ceftriaxone. Four previously published random-
ized trials of children also did not show statistical differ-
ences in the incidence of scars according to the way of
administration (oral versus intravenous) or the duration
of intravenous administration (Table 6).20–23 One study
included severe uropathies22 and 2 only patients with
APN lesions demonstrated by DMSA scan.21,22 Hoberman
et al20 compared 14 days of oral cefixime and 3 days of
intravenous cefotaxime followed 11 days of oral ce-
fixime but included very young patients. Most of pa-
tients presented milder inflammatory conditions com-
pared with our data. In the study of Benador et al,21 the
age groups of the 2 arms were different and the final
DMSA scan was performed early, at 3 months. The 2

TABLE 6 Summary of the Published Randomized Studies That Compared the Incidence of Scars at DMSA Scan According to Antibiotic
Treatment Modalities
Study Inclusion Criteria N Age, mean Randomized Treatment % of Patients With Scars
(Duration, d) on DMSA Scan
Hoberman et al20 (1995) Clinical (fever ⬎ 38.3°C) 306 8.8 mo Oral (14) 9.8
8.3 mo Intravenous (3)/oral (11) 7.2
Benador et al21 (2001) APN confirmed by DMSA scan 229 2.4 y (median) Intravenous (3)/oral (12) 36
1.0 y (median) Intravenous (10)/oral (5) 33
Levtchenko et al23 (2001) Clinical (fever ⬎ 38.3°C) 87 20.0 mo Intravenous (3)/oral (18) 25
Elevated CRP 87 25.0 mo Intravenous (7)/oral (14) 18
Vilaichone et al22 (2001) APN confirmed by DMSA scan (including 36 26.0 mo Intravenous (3)/oral (7) 66
high-grade VUR) 14.0 mo Intravenous (10) 61
This study Clinical (fever ⬎ 38.5°C) 386 37.0 mo Intravenous (3)/oral (5) 13
CRP ⬎ 20 mg/L 386 31.0 mo Intravenous (8) 17

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other trials included a limited number of patients com-
pared with the other studies.22,23
The overall percentage of patients with renal scars in
our series was 15%. This is slightly more than the ⬃9%
reported by Hoberman et al20; however, it is far less than
the percentages of ⬃20% to 60% reported in the 3 other
series.21–23 The low percentage in our series and in the
series by Hoberman et al20 might be for the following
reasons: (1) inclusion criteria did not take into account
the results of an initial DMSA scintigraphy, thus includ-
ing up to 30% to 40% of patients who had no initial
parenchymal involvement; (2) in our series, a careful
selection of patients was done with exclusion of those
with renal hypoplasia/dysplasia or severe uropathy,
which was not the case in previous studies; (3) we
excluded the patients who had fever for ⬎4 days or
recurrent APN; (4) DMSA scan was performed 6 to 9
months after the APN episode; the recovery of renal
defect is slow,32 and DMSA scans performed at 3
months33 may have included reversible lesions; and (5)
there is a possible beneficial role of the initial double
antibiotic used in our patients, with 2 days aminoglyco-
side in addition to ceftriaxone monotherapy. Neverthe-
less, one may notice than no aminoglycoside was used in
trial by Hoberman et al, with results similar to ours.
It is interesting that the overall duration of 8 days of
antibiotic treatment in our study is the shortest ever
used. Despite this, the percentage of patients with resid-
ual renal damage is 1 of the lowest reported. This opens
the way to new prospective, randomized studies to es-
tablish the minimal treatment duration when antibiotics
whose concentration remains above the minimal inhib-
itor concentration for a long time, such as third-gener-
ation cephalosporins, are used.33,34
The role of VUR in the development of renal scars
remains controversial.35–37 However, some recent pro-
spective studies using late DMSA scan for children with
APN showed a significant association between the pres-
ence of VUR and the risk for residual scars.38,39
The frequency of scars increases with the grade of VUR,
and congenital dysplasia lesions that are associated with
high-grade VUR cannot be differentiated from acquired
postinfection scars.40–44 Because we excluded patients with
grade 4 or 5 VUR from our study, this difficulty of DMSA
scan interpretation was partly eliminated. Nevertheless, in
patients with grade 3 VUR, we observed a significantly
higher incidence of scars as DMSA demonstrated by scan.
Because no DMSA scan was done initially for comparison,
we cannot be sure of the respective role of infection or
dysplasia in these patients. In experimental data, the inten-
sity of the inflammatory response is determinant for the
development of scars after APN.45 Our data, for the first
time, indirectly confirmed this risk factor. We demonstrated
that enlarged kidneys at onset, which reflects renal inflam-
mation, is associated with an increased risk for renal scars.
CONCLUSIONS
In our study, long (8 days) intravenous treatment with
ceftriaxone did not seem to reduce the risk for renal scars
compared with short (3 days) intravenous treatment.
We confirm that long intravenous treatment is no longer
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indicated for children with APN and that an antibiotic
course of 8 days is safe when powerful antibiotic such as
ceftriaxone/cefotaxime is used. The next step will be the
comparison of oral versus short intravenous followed by
oral treatment to confirm the results of Hoberman et al.20
DMSA scan, the gold standard to evaluate renal scars,
does not preclude the difficulty of differentiating renal
dysplasia from acquired postinfection scars. The recent
advances in urinary proteome analysis might allow the
identification of urinary markers for renal scars.46 Such a
noninvasive approach would allow repetitive evaluation
of the progression of renal scars in APN in children.
ACKNOWLEDGMENTS
This study was registered by the Commission Nationale de
l’Informatique et des Libertés (CNIL 999203) and accepted
by the ethics committee of Purpan University Hospital of
Toulouse. This study was supported by Program Hospitalier
de Recherche Clinique from the French Ministry of Health
(9780 N) and a grant from the Roche Laboratory.
We gratefully acknowledge the French Society of Nu-
clear Medicine and Molecular Imaging, French Society of
Pediatric Nephrology, for help and the colleagues who
participated in this study: S. Decramer and C. Azéma (Hô-
pital des Enfants, Toulouse), B. Roussel (American Memo-
rial Hospital, Reims, Lille), B. Novo (Hôpital Jeanne de
Flandre, Lille), D. Morin (Hôpital Armand de Villeneuve,
Montpellier), M. P. Lavocat (Pédiatrie, CHU Saint Etienne),
B. Parchoux (Hôpital Debrousse, Lyon), C. Guyot (Hôpital
Mère Enfant, Nantes), S. Taque (Pédiatrie, CHU Rennes),
M. Fischbach (Hôpital Hautepierre, Strasbourg), J. B. Pal-
coux (Hotel Dieu, Clermont Ferrand), B. Bader-Meunier
(Hôpital Kremlin Bicêtre, Bicêtre), C. Loirat and V. Leroy
(Hôpital Robert Debré, Paris), J. L. André (Hôpital
d’Enfants, Nancy), R. Salomon (Hôpital des Enfants
Malades, Paris), P. Cochat (Hôpital Edouard Herriot, Lyon),
B. Boudailliez (Pédiatrie, CHU Amiens), and G. Champion
(Pédiatrie, CHU Angers).
DMSA scintigraphies were interpreted by E. Ouhay-
oun, F. Bouissou (CHU Toulouse), F. Archambaud (Hô-
pital Kremlin-Bicètre, Bicêtre), and A. Sergent-Alaoui
(Hôpital Trousseau, Paris), and statistical analysis was
performed by Caroline Munzer, Sylvie Cassadou, and
Marie Bourjot (Hôpital des Enfants, Laboratoire
d’Epidémiologie, Toulouse). We thank Joost P. Schan-
stra and Chantal Loirat for editorial assistance.
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 Prospective, Randomized Trial Comparing Short and Long Intravenous
Antibiotic Treatment of Acute Pyelonephritis in Children: Dimercaptosuccinic
Acid Scintigraphic Evaluation at 9 Months
François Bouissou, Caroline Munzer, Stéphane Decramer, Bernard Roussel, Robert
Novo, Denis Morin, Marie Pierre Lavocat, Claude Guyot, Sophie Taque, Michel
Fischbach, Eric Ouhayoun, on behalf of the French Society of Nuclear Medicine and
Molecular Imaging, Chantal Loirat and on behalf of the French Society of Pediatric
Nephrology
Pediatrics published online Feb 11, 2008;
DOI: 10.1542/peds.2006-3632
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