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DOI:10.1542/peds.2006-3632published online Feb 11, 2008;Pediatrics

NephrologyMolecular Imaging, Chantal Loirat and on behalf of the French Society of Pediatric

Fischbach, Eric Ouhayoun, on behalf of the French Society of Nuclear Medicine andNovo, Denis Morin, Marie Pierre Lavocat, Claude Guyot, Sophie Taque, Michel

Franois Bouissou, Caroline Munzer, Stphane Decramer, Bernard Roussel, RobertAcid Scintigraphic Evaluation at 9 Months

Antibiotic Treatment of Acute Pyelonephritis in Children: DimercaptosuccinicProspective, Randomized Trial Comparing Short and Long Intravenous

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The online version of this article, along with updated information and services, is

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. Alland trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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ARTICLE

Prospective, Randomized Trial Comparing Short and

Long Intravenous Antibiotic Treatment of AcutePyelonephritis in Children: Dimercaptosuccinic AcidScintigraphic Evaluation at 9 Months

Francois Bouissou,MDa, CarolineMunzer, PhDa, StephaneDecramer,MDa, Bernard Roussel,MDb, RobertNovo,MDc, DenisMorin,MDd,

MariePierreLavocat,MDe, ClaudeGuyot, MDf, SophieTaque, MDg, MichelFischbach, MDh, Eric Ouhayoun, MDi, onbehalf of the

FrenchSociety ofNuclear Medicine andMolecular Imaging, Chantal Loirat, MDj, on behalfof the FrenchSociety of PediatricNephrology

aNephrologie Pediatrique, Hopital des Enfants, Universite Paul Sabathier, Centre Hospitalier Universita ire Purpan, Toulouse, France; bNephrologie Pediatrique, American

Memorial Hospital, Centre Hospitalier Universitaire Reims, Beims, France; cNephrologie Pediatrique, Hopital Jeanne de Flandre, Universite Lille 2, Centre Hospitalier

Regional Universitaire Lille, Lille, France; dNephrologie Pediatrique, Hopital Arnaud de Villeneuve, Universite Montpellier I, Centre Hospitalier Universitaire Montpellier,

Montpellier, France; eNephrologie Pediatrique, Centre Hospitalier Universitaire Saint Etienne, Saint Etienne, France; fNephrologie Pediatrique, Hopital Mere Enfant ,

Universite de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France; gNephrologie Pedi atrique, Centre Hospitalier Universitaire Rennes, Rennes, France;hNephrologie Pediatrique, Hopital Hautepierre, Universite Louis Pasteur, Centre Hospitalier Universita ire Strasbourg, Strasbourg, France; iMedecine Nuclea ire, Universite

Paul Sabathier, Centre Hospitalier Universitaire Purpan Toulouse, Toulouse, France; jService de Nephrologie, Facul te de Medecine Denis Diderot, Universite Paris VII,

Hopital Robert Debre, Assistance Publique-Hopitaux 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 theeffect of 3 vs 8 days of intravenous ceftriaxone treatment on the incidence of renalscarring at 6 to 9 months of follow-up in 383 children with a first episode of acutepyelonephritis.

METHODS. After initial treatment with intravenous netilmicin and ceftriaxone, patients

were randomly assigned to either 5 days of oral antibiotics (short intravenoustreatment) or 5 days of intravenous ceftriaxone (long intravenous treatment). In-clusion criteria were age 3 months to 16 years and first acute pyelonephritis episode,defined by fever of 38.5C, C-reactive protein level of 20 mg/L, and bacteriuria at105/mL. All patients underwent 99m technetium-dimercaptosuccinic acid scintig-raphy 6 to 9 months after inclusion. A total of 548 children were included, 48 ofwhom were secondarily excluded and 117 of whom were lost to follow-up or hadincomplete data; therefore, 383 children were eligible, 205 of them in the shortintravenous treatment group and 178 in the long intravenous treatment group.

RESULTS. At inclusion, median age was 15 months, median duration of fever was 43hours, and median C-reactive protein level was 122 mg/L. A total of 37% (143 of383) of patients had a vesicoureteral reflux grades 1 to 3. Patient characteristics atinclusion were similar in both groups, except for a significantly higher proportion of

girls in the short intravenous treatment group. The frequency of renal scars atscintigraphy was similar in both groups. Multivariate analysis demonstrated thatrenal 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 intravenousceftriaxone. Increased renal height at initial ultrasound examination and grade 3 vesicoureteric reflux were signif-icant risk factors for renal scars.

ACUTE PYELONEPHRITIS (APN) is common in children and infants, with an estimated incidence of 1.28 per 1000 in girlsand 0.18 per 1000 in boys younger than 14 years and a prevalence in febrile infants of 5.3%.13 APN can induceirreversible renal scars, with a risk for hypertension or chronic renal failure at long-term follow-up. 47 With the use of

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peds.2006-3632

doi:10.1542/peds.2006-3632

KeyWords

children, acute pyelonephritis, antibiotics,DMSA scintigraphy

Abbreviations

APNacute pyelonephritis

DMSAdimercaptosuccinic acid

VURvesicoureteral reflux

CRPC-reactive protein99mTc99m technetium

ORodds ratio

Accepted for publication Aug 1, 2007

Address correspondence to Francois Bouissou,

MD, Nep hrologie Ped iatrique , Hop ital des

Enfants, TSA70034, Avenue de Grande

Bretagne, 31059 Toulouse Cedex 6, France.

E-mail: [email protected]

PEDIATRICS (ISSNNumbers:Print, 0031-4005;

Online, 1098-4275). Copyright 2008by theAmericanAcademy of Pediatrics

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dimercaptosuccinic acid (DMSA) scans, currently the bestway to detect renal scars,810 the percentage of residualrenal scars after 1 APN episode has been shown to vary

between 25% and 60%.11,12 This variability is attributableto the heterogeneity of the populations studied and thedifficulty 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 antibioticsdepends of the bacterial ecology and may vary from 1country to another.13,14 Monotherapy or bitherapy can beused. Whether the duration and the way of administrationof antibiotics influence the risk for renal scars is debated.Furthermore, general practice was shown to differ widelyfrom 1 pediatric team to another.1518 Only a limited num-

ber of prospective, randomized studies have been report-ed.19 In 1999, the study by Hoberman et al20 found nosignificant differences in persistent renal damage at 6months between oral cefotaxime therapy (14 days) andintravenous therapy (3 days) followed by oral therapy (10days). Three other trials found no significant differences in

persistent renal damage between intravenous therapy (34days) followed by oral therapy and intravenous therapy for7 to 14 days.2123 Concerns persist about the percentage ofresidual scars, and trials still are required to confirm thatoral cefixime or short courses of intravenous therapy fol-lowed by oral therapy are sufficient to limit the risk forrenal damage and to determine the optimal total durationof therapy.20

We report a prospective, randomized, multicenter (17centers) 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 (50mg/kg for 3 days), followed either by 5 days of intrave-nous ceftriaxone in long treatment group or by 5 days oforal antibiotic in short treatment group. The end pointwas to compare the frequency of renal scars on DMSAscan 6 to 9 months later. Considering the difficulty indifferentiating acquired or congenital scars, we excludedpatients with known uropathy, obstructive uropathy orvesicoureteral reflux (VUR) grades 4 and 5.

METHODS

Patient SelectionInclusion criteria were age between 3 months and 16year; first acute episode of APN, defined by fever of38.5C, 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 16years; known patients followed for any kind of uropa-thy; previous urinary tract infection; new patients withobstructive uropathy (pelvis dilation 10 mm) or renalhypoplasia/dysplasia (kidney height 2 SD) at initialultrasound examination; urine culture positive for

Pseudomonas aeruginosa, Staphylococcus, or group D Strep-tococcus; fever of 38.5C for 4 days at admission; orconcomitant nonurinary infection. Patients who were

judged by the physician to be severally ill were excludedfrom randomization. Secondary exclusion criteria werehigh-grade VUR (more than grade 3), detected at cys-tography, or APN recurrence during the period untilDMSA scintigraphy.

All eligible patients were included and randomly as-signed after informed consent was obtained from parentsand children when old enough.

TreatmentsTotal duration of antibiotic treatment was 8 days in bothgroups. 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 torandomization, patients subsequently received either 5days of oral antibiotic according to the organisms 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.

InvestigationsAt admission, a urine specimen was collected in a sterile

bag in young children or by midstream catch in olderchildren for dipstick for leukocyte esterase and nitrite,white blood cell count, Gram stain, and urine culture.Blood sample was collected for blood cell count, serumcreatinine and CRP levels, and blood culture). Renal andurinary tract ultrasound examination with renal height

measurement was performed before randomization. Weconsidered a kidney to be enlarged when the kidneyheight was 1.5 cm above normal for age.

At 15 to 30 days, all patients underwent a voidingcystography (results: no reflux or reflux graded accord-ing to the international classification, grade 15).

Between 6 and 9 months (median: 8.35), a 99mtechnetium (99mTc)-DMSA scintigraphy was performedaccording to the protocol of Mackenzie24: intravenous99mTc-DMSA dosage was adapted to weight (EuropeanTask Force recommendations25), and acquisition wasperformed 2 to 4 hours later, at 4 angles of incidence(anterior, posterior, oblique right, and oblique left) with256 256 matrix during 5 minutes. In the youngestpatients, a pinhole was used and acquisition time wasprolonged 10 minutes. All biophysical centers were re-quired to test the quality of DMSA radiopharmaceuticaland to control the camera according to the recommen-dations of the French Society of Biophysics and NuclearMedicine. The relative percentage of DMSA fixation ofeach kidney was calculated, and all pictures were sent tothe coordination center for qualitative interpretation.The defects of DMSA fixation were evaluated accordingto criteria of Patel et al.26 Cortical defect or heteroge-neous parenchymal uptake, with or without renal shapemodification, was considered as scar. During the follow-up, urinalysis was required in case of intercurrent fever.

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Running ProtocolThe inclusion period was from January 1999 to June2002, and follow-up ended in June 2003. The random-ization (random tables) was centralized and stratified bycenter, by blocks of 20 numbered sealed opaque enve-lopes with equal numbers of treatment assignments.Allocation was done by the local investigator by openinga numbered sealed envelope 48 hours after admissionand after informed consent by the parents.

All recorded data were completed by a local investi-gator and were sent to the coordination center. Data

were registered in a computer base according to thefrench legislation (Commission nationale de linfor-matique et des libertes), on Epi Info software (Centersfor Disease Control and Prevention, Atlanta, GA). AllDMSA scans were reviewed (quality of the scan, size,shape, cortical or medullar defect, localization, num-

ber of defects, unilateral or bilateral) in December2003 by a group of 4 independent biophysicians, with-out knowledge of treatment group. In case of disagree-ment, DMSA scans were reanalyzed in a commonsession.

EnrollmentJanuary 99June 2002

Assessed for eligibility: 802(first APN episode,no known uropathy,

no obstructive uropathy or renal

hypoplasia on initial ultrasound)

Parental refusal:

254

Randomly

assigned:

Short IV: 277 Long IV: 271

Secondary exclusion:

22

APN recurrence: 15

Severe uropathy: 7

(VUR grade 4 or 5 )

Secondary

exclusion: 26

APN recurrence: 17

Severe uropathy: 9(VUR grade 4 or 5 )

Analyzed: 205 Analyzed: 178

Incomplete

data: 67

Lost to follow-up:50

DMSA refusal:17

Incomplete

data: 50

Lost to follow-up:37

DMSA refusal:13

548

FIGURE 1

Consort diagram.


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StatisticalAnalysisThe sample size was calculated to demonstrate a differ-ence of 10% in the percentage of renal scars between the2 groups ( risk: 5%; power: 80%; 2-sided hypothesistest). The size needed was 493 patients. All analyseswere performed by using Epi Info and Stata (Stata Corp,College Station, TX) software in intention to treat.

Odds ratios (ORs) and 95% confidence intervals wereestimated by using unconditional logistic regressionmodels. Adjustment for potential confounding factorssuch as gender and age and mutual adjustments were

tested.2731

RESULTS

Demographic andPopulationCharacteristicsDuring the enrollment period, 802 children were eligible,548 of whom were included and allocated to 1 of the 2groups after randomization; 165 of these 548 patients werenot analyzed: 117 because of incomplete data (nonatten-dance at last visit in 87, parental refusal of DMSA scan in30) and 48 because of secondary exclusion (recurrence of

APN in 32, grade 4 or 5 VUR in 16). The proportion ofnonanalyzed patients was comparable in the 2 groups

(short treatment group: 26% [72 of 277]; long treatmentgroup: 34% [93 of 271]; P .12). Finally, 383 patients

were analyzed at the end of the study: 205 in the shorttreatment group and 178 in the long treatment group (Fig

1). Patient characteristics were comparable between the 2groups, except for a higher proportion of girls in short

treatment group (Tables 1 and 2). Gender was similarlydistributed 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 Escherichiacoli in 97% (200 of 205) of patients in the short treatmentgroup and 96% (172 of 178) in the long treatment group

(not significant). In the short treatment group, the oralantibiotic 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 1 Patient Characteristics at Inclusion

Characteristic Total

Population

Short Treatment

Group

Long Treatment

Group

No. of patients 383 205 178

No. of patients per center

Mean 23 12 11

Median (range) 27 (258) 14 (129) 13 (129)

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 (3191) 17 (3191) 13 (3171)

Fever duration before therapy, h

Mean 46 44 48

Median (range) 43 (0162) 38 (0162) 45 (0146)

Highest body temperature, C

Mean 39.7 39.7 39.8

Median (range) 40.0 (38.141.7) 40.0 (38.141.0) 40.0 (38.541.7)

CRP, mg/L

Mean 122 117 128

Median (range) 100 (20890) 101 (21739) 100 (20890)

a P .001.

TABLE 2 Initial RadiologicFindings

Finding Total Population(N 383)

Short TreatmentGroup (n 205)

Long TreatmentGroup (n 178)

Ultrasound examination

Kidney height, cm

Mean 7.1 7.0 7.1

Median (range) 7.0 (512) 7.0 (5.012.0) 7.0 (5.011.0)

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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was also similar (Table 2). All population characteris-tics were similar in analyzed and nonanalyzed patients(data not shown). DMSA scintigraphs showed renalscars in 15% of patients (57 of 383), most often focal(Table 3).

Comparison Between the2 TreatmentGroupsThe presence of scars was slightly higher in the longtreatment 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-

ent hypothesis and confirmed that long (8 days) intra-venous treatment with ceftriaxone did not seem toreduce the risk for renal scars compared with short (3days) intravenous treatment. Analysis in secondarily ex-cluded patients gave similar results (data not shown).

Risk Factors for Renal ScarsThe correlations between the presence of scars and dif-ferent variables of interest are indicated in Table 4. Bi-variate analysis indicated that scars were significantlymore frequent in patients with VUR grades 2 and 3, in

TABLE 3 Results of99mTc-DMSAScintigraphy

Parameter Total Population

(N 383)

Short Treatment

Group (n 205)

Long Treatment

Group (n 178)

OR (95% CI)

Scars, n (%) 57 (15) 26 (13) 31 (17) 1.45 (0.792.67)

Focal cortical defects, n (%) 25 (7)a 12 (5.8) 11 (6.1) 1.27 (0.533.06)

Upper pole, n 14 7 7

Median , n 0 0 0

Lower pole, n 9 5 4

Heterogeneous parenchymal

defects, n (%)

21 (5.5)a 10 (4.8) 11 (6.1) 1.28 (0.493.36)


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 (0.573.43)


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.

TABLE 4 Risk Factors of Renal Scars, BivariateAnalysisRisk Factor Renal Scars

(N 57), n (%)

No Scars

(N 326), n (%)

OR 95% CI P

Age, mo

18 28 (49) 191 (59) 1.47 0.802.69 .180

18 29 (51) 135 (41)

Boys 11 (19) 75 (23) 1.25 0.592.72 .530

Girls 46 (81) 251 (77)

Delay of antibiotic therapy, d

2 27 (47) 178 (55) 1.34 0.732.45 .310

2 30 (53) 148 (45)

Fever duration, d

3 20 (35) 146 (45) 1.50 0.802.83 .170

3 37 (65) 180 (55)

CRP, mg/L100 21 (37) 169 (52) 1.85 1.003.45 .030

100 36 (63) 157 (48)

VUR

No 26 (46) 214 (65) 1.0 Reference

Yes 31 (54) 112 (34) 2.28 1.244.21 .004

Grade

1 5 (9) 27 (8) 1.52 0.544.28 .430

2 17 (30) 69 (21) 2.02 1.033.94 .040

3 9 (16) 16 (5) 4.60 1.8511.48 .001,.010a

Initial kidney height

Normal 52 (91) 316 (97)

Enlargedb 5 (9) 10 (3) 3.04 0.8610.29 .050

a For trend.b More than 1.5 cm over normal height for age.


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patients with CRP levels of 100 mg/L, and when initialultrasound showed enlarged kidney(s). The presence ofscars was independent of age, gender, delay of antibiotictreatment, and total fever duration.

Multivariate analysis (Table 5) confirmed that theincidence of scars was significantly correlated with thepresence of VUR. The risk significantly increased withthe grade (grade 1 OR: 1.42; grade 2 OR: 1.72; grade 3OR: 4.61; P .002 for trend). Enlarged kidney at initial

ultrasound examination was also significantly correlatedto the risk for scars (OR: 3.19). Adjustment for potentialconfounding factors such as gender and age did notchange the results. Estimations remained unchanged af-ter mutual adjustments for the different variables ofinterest, although CRP levels of 100 mg/L no longerappeared as a risk factor for scars (Table 2).

DISCUSSION

Only 4 randomized studies that compared the incidenceof renal scars as demonstrated by DMSA scintigraphyaccording to antibiotic treatment modalities in childrenwith APN have been published.2023 Our study is the

largest prospective trial performed in children with APN.The multicenter setup of this study allowed the inclusionof a large number of children without severe uropathy atthe first episode of APN. We showed that the incidenceof permanent renal damage is similar in children whoreceived 8 days intravenous treatment and in those whoreceived 3 days intravenous treatment followed by 5days of oral antibiotic; however, several points of ourstudy need to be discussed.

First because of the number of incomplete data andsecondary exclusion, this study did not have sufficient

power to detect a superiority of 1 treatment modalityover the other. Nevertheless, sensitivity analysis showedthat if 1 treatment was better than the other, then itwould be the short treatment.

Second, the bacteriologic test was done on urine thatwas collected with sterile bags for young children, withan increased risk for false-positive bacteriuria. However,this risk was equally distributed between the 2 groups,

and positive results with several types of colonies aturine culture were discarded.

Third, our 2 study groups were similar except for asignificantly higher proportion of boys in the long intra-venous treatment group, but age, degree and duration offever before treatment initiation, CRP, proportion ofchildren with VUR, and VUR grades were nonsignifi-cantly different between the 2 groups. In addition, esti-mations remained unchanged in multivariate analysesthat included gender.

For minimization of the patients irradiation burdenand the cost of the study, the inclusion criteria were onlyclinical and bacteriologic. We chose to perform only a

late DMSA scintigraphy to detect residual scars; there-fore, patients with no initial parenchymal lesions of APNwere most probably included. Nevertheless, the propor-tion of patients with febrile urinary tract infection with-out APN as demonstrated by DMSA scintigraphy isknown to be 30%20,21,23 and must have been equallydistributed between the 2 groups.

Here we showed that the incidence of permanentrenal damage in children after a first episode of APN wassimilar 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 durationof intravenous administration (Table 6).2023 One studyincluded severe uropathies22 and 2 only patients withAPN lesions demonstrated by DMSA scan.21,22 Hobermanet al20 compared 14 days of oral cefixime and 3 days ofintravenous 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 theage groups of the 2 arms were different and the finalDMSA scan was performed early, at 3 months. The 2

TABLE 5 RiskFactors of RenalScars: Multivariate Analysis

Parameter OR 95% CI P

VUR grade

0 Reference

1 1.42 0.504.03 .510

2 1.72 0.873.40 .120

3 4.61 1.8411.57 .001,.002a

Enlarged kidney on initial ultrasound 3.19 1.0010.16 .049

CRP 100 mg/L 1.71 0.943.08 .075

a For trend.

TABLE 6 Summary of thePublished Randomized Studies That Compared theIncidence of Scars at DMSA Scan AccordingtoAntibioticTreatmentModalities

Study Inclusion Criteria N Age, mean RandomizedTreatment

(Duration, d)

% of Patients With Scars

on DMSA Scan

Hoberman et al20 (1995) Clinical (fever 38.3C) 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 38.3C) 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 38.5C) 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 inour series was 15%. This is slightly more than the 9%reported by Hoberman et al20; however, it is far less thanthe percentages of 20% to 60% reported in the 3 otherseries.2123 The low percentage in our series and in theseries by Hoberman et al20 might be for the following

reasons: (1) inclusion criteria did not take into accountthe results of an initial DMSA scintigraphy, thus includ-ing up to 30% to 40% of patients who had no initialparenchymal involvement; (2) in our series, a carefulselection of patients was done with exclusion of thosewith renal hypoplasia/dysplasia or severe uropathy,which was not the case in previous studies; (3) weexcluded the patients who had fever for 4 days orrecurrent APN; (4) DMSA scan was performed 6 to 9months after the APN episode; the recovery of renaldefect is slow,32 and DMSA scans performed at 3months33 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 intrial by Hoberman et al, with results similar to ours.

It is interesting that the overall duration of 8 days ofantibiotic treatment in our study is the shortest everused. Despite this, the percentage of patients with resid-ual renal damage is 1 of the lowest reported. This opensthe way to new prospective, randomized studies to es-tablish the minimal treatment duration when antibioticswhose 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 scarsremains controversial.3537 However, some recent pro-spective studies using late DMSA scan for children withAPN 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 withhigh-grade VUR cannot be differentiated from acquiredpostinfection scars.4044 Because we excluded patients withgrade 4 or 5 VUR from our study, this difficulty of DMSAscan interpretation was partly eliminated. Nevertheless, inpatients with grade 3 VUR, we observed a significantlyhigher 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 ordysplasia in these patients. In experimental data, the inten-sity of the inflammatory response is determinant for thedevelopment of scars after APN.45 Our data, for the firsttime, indirectly confirmed this risk factor. We demonstratedthat 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 withceftriaxone did not seem to reduce the risk for renal scarscompared with short (3 days) intravenous treatment.We confirm that long intravenous treatment is no longer

indicated for children with APN and that an antibioticcourse of 8 days is safe when powerful antibiotic such asceftriaxone/cefotaxime is used. The next step will be thecomparison of oral versus short intravenous followed byoral 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 renaldysplasia from acquired postinfection scars. The recent

advances in urinary proteome analysis might allow theidentification of urinary markers for renal scars.46 Such anoninvasive approach would allow repetitive evaluationof the progression of renal scars in APN in children.

ACKNOWLEDGMENTS

This study was registered by the Commission Nationale delInformatique et des Libertes (CNIL 999203) and accepted

by the ethics committee of Purpan University Hospital ofToulouse. This study was supported by Program Hospitalierde 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 ofPediatric Nephrology, for help and the colleagues whoparticipated in this study: S. Decramer and C. Azema (Ho-pital des Enfants, Toulouse), B. Roussel (American Memo-rial Hospital, Reims, Lille), B. Novo (Hopital Jeanne deFlandre, Lille), D. Morin (Hopital Armand de Villeneuve,Montpellier), M. P. Lavocat (Pediatrie, CHU Saint Etienne),B. Parchoux (Hopital Debrousse, Lyon), C. Guyot (HopitalMere Enfant, Nantes), S. Taque (Pediatrie, CHU Rennes),M. Fischbach (Hopital Hautepierre, Strasbourg), J. B. Pal-coux (Hotel Dieu, Clermont Ferrand), B. Bader-Meunier(Hopital Kremlin Bicetre, Bicetre), C. Loirat and V. Leroy(Hopital Robert Debre, Paris), J. L. Andre (Hopital

dEnfants, Nancy), R. Salomon (Hopital des EnfantsMalades, Paris), P. Cochat (Hopital Edouard Herriot, Lyon),B. Boudailliez (Pediatrie, CHU Amiens), and G. Champion(Pediatrie, CHU Angers).

DMSA scintigraphies were interpreted by E. Ouhay-oun, F. Bouissou (CHU Toulouse), F. Archambaud (Ho-pital Kremlin-Bicetre, Bicetre), and A. Sergent-Alaoui(Hopital Trousseau, Paris), and statistical analysis wasperformed by Caroline Munzer, Sylvie Cassadou, andMarie Bourjot (Hopital des Enfants, LaboratoiredEpidemiologie, Toulouse). We thank Joost P. Schan-stra and Chantal Loirat for editorial assistance.

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DOI:10.1542/peds.2006-3632published online Feb 11, 2008;Pediatrics

NephrologyMolecular Imaging, Chantal Loirat and on behalf of the French Society of PediatricFischbach, Eric Ouhayoun, on behalf of the French Society of Nuclear Medicine and

Novo, Denis Morin, Marie Pierre Lavocat, Claude Guyot, Sophie Taque, MichelFranois Bouissou, Caroline Munzer, Stphane Decramer, Bernard Roussel, Robert

Acid Scintigraphic Evaluation at 9 MonthsAntibiotic Treatment of Acute Pyelonephritis in Children: Dimercaptosuccinic

Prospective, Randomized Trial Comparing Short and Long Intravenous

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