Randomized Trial of Oral Versus Sequential IV/Oral Antibiotic for Acute Pyelonephritis in Children Nathalie Bocquet, Aline Sergent

Alaoui, Jean-Pierre Jais, Vincent Gajdos, Vincent Guigonis, Bernard Lacour and Grard Chron Pediatrics 2012;129;e269; originally published online January 30, 2012; DOI: 10.1542/peds.2011-0814

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Randomized Trial of Oral Versus Sequential IV/Oral Antibiotic for Acute Pyelonephritis in Children Nathalie Bocquet, Aline Sergent Alaoui, Jean-Pierre Jais, Vincent Gajdos, Vincent Guigonis, Bernard Lacour and Grard Chron Pediatrics 2012;129;e269; originally published online January 30, 2012; DOI: 10.1542/peds.2011-0814
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ARTICLE

Randomized Trial of Oral Versus Sequential IV/Oral Antibiotic for Acute Pyelonephritis in Children
AUTHORS: Nathalie Bocquet, MD,a Aline Sergent Alaoui, MD,b Jean-Pierre Jais, MD, PhD,c,d Vincent Gajdos, MD,e Vincent Guigonis, MD,f Bernard Lacour, MD, PhD,d,g and Grard Chron, MD, PhDa,d
aAssistance Publique-Hpitaux de Paris, Hpital Necker Enfants Malades, Service des Urgences Pdiatriques, Paris, France; bAssistance Publique-Hpitaux de Paris, Hpital Armand Trousseau, Service de Mdecine Nuclaire, Paris, France; cAssistance Publique-Hpitaux de Paris Service de Biostatistique, Hpital Necker Enfants Malades, Paris, France; dUniversit Paris Descartes, Paris, France; eAssistance Publique-Hpitaux de Paris, Service de Pdiatrie, Hpital Antoine Bclre, Clamart, France; fService de Pdiatrie, Hpital Universitaire Dupuytren, Limoges, France; and gAssistance Publique-Hpitaux de Paris, Service de Biochimie A, Hpital Necker Enfants Malades, Paris, France

WHATS KNOWN ON THIS SUBJECT: The standard initial management for infants and children with acute pyelonephritis is intravenous antibiotic treatment. WHAT THIS STUDY ADDS: Our results support the use of an oral cexime treatment of initial episodes of acute pyelonephritis involving a gram-negative bacteria strain in children aged 1 month to 3 years who are without urological abnormalities and without clinical hemodynamic impairment.

KEY WORDS acute pyelonephritis, pediatric, procalcitonin, renal scarring ABBREVIATIONS APNacute pyelonephritis CIcondence interval DMSAdimercaptosuccinic acid EDemergency department ITTintention to treat PCTprocalcitonin PPAper protocol analysis UTIsurinary tract infections VCGvoiding cystography VURvesicoureteral reux All authors brought substantial contributions to conception and design of the study and to acquisition of data; Dr Jais did all statistical analysis. This trial has been registered at www.clinicaltrials.gov (identier NCT00136656). www.pediatrics.org/cgi/doi/10.1542/peds.2011-0814 doi:10.1542/peds.2011-0814 Accepted for publication Oct 10, 2011 Address correspondence to Grard Chron, MD, PhD, Hpital Necker Enfants Malades, Service des Urgences pdiatriques, 149 rue de Svres, 75743 PARIS Cedex 15, France. E-mail: gerard. cheron@nck.aphp.fr PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2012 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Gajdos reports receiving consulting fees from GlaxoSmithKline; the other authors have indicated they have no nancial relationships relevant to this article to disclose.

abstract
OBJECTIVE: To conrm whether oral antibiotic treatment is as efcacious as sequential intravenous/oral antibiotic treatment in the prevention of renal scarring in children with acute pyelonephritis and scintigraphy-documented acute lesions. METHODS: In a prospective multicenter trial, children aged 1 to 36 months with their rst case of acute pyelonephritis, a serum procalcitonin concentration $0.5 ng/mL, no known uropathy, and a normal ultrasound exam were randomized into 2 treatment groups. They received either oral cexime for 10 days or intravenous ceftriaxone for 4 days followed by oral cexime for 6 days. Patients with acute renal lesions detected on early dimercaptosuccinic acid scintigraphy underwent a follow-up scintigraphy 6 to 8 months later. RESULTS: The study included 171 infants and children. There were no signicant differences between the 2 groups in any clinical characteristic. Initial scintigraphy results were abnormal for 119 children. Ninety-six children were measured for renal scarring at the followup scintigraphy (per protocol analysis population). The incidence of renal scarring was 30.8% in the oral treatment group and 27.3% for children who received the sequential treatment. CONCLUSIONS: Although this trial does not statistically demonstrate the noninferiority of oral treatment compared with the sequential treatment, our study conrmed the results of previously published reports and therefore supports the use of an oral antibiotic treatment of primary episodes of acute pyelonephritis in infants and young children. Pediatrics 2012;129:e269e275

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Urinary tract infections (UTIs) are common in childhood. UTIs affect up to 3.5% of children in the United States annually.1 Febrile UTI is a serious bacterial infection because of its potential to produce renal scarring. Not all febrile UTIs are acute pyelonephritis (APN); only up to two-thirds of children with a UTI accompanied by fever have acute parenchymal infection, with acute lesions on dimercaptosuccinic acid (DMSA) scintigraphy, 26 which is the denitive diagnosis of APN.68 A serum procalcitonin (PCT) concentration . 0.5 ng/mL predicts renal involvement. 6,9 11 The standard initial treatment of infants and children with APN has been intravenous antibiotic treatment. In a recent Cochrane review, Hodson et al reported that there were no signicant differences in the risk of renal scarring between long intravenous treatment (815 days) and a sequential treatment consisting of intravenous antibiotics (2 4 days) followed by oral treatment.8 Three prospective trials have suggested that children with APN could receive an entirely oral antibiotic treatment without increased risk of renal scarring 6 to 12 months later.24 However, children receive different treatments in different parts of the world and also in different regions of the same country.12,13 Our hypothesis was that oral antibiotic treatment is as equally efcacious as sequential treatment with respect to the presence of renal scarring 6 to 8 months later in 1- to 36-month-old children with APN and scintigraphydocumented acute lesions.

April 2008. The study was conducted with approval obtained from the Ethics Committee of the Direction de la Recherche Clinique. Written informed consent was obtained from both parents. Inclusion Criteria Infants and children, aged 1 to 36 months, were recruited from patients who presented at an emergency department (ED) with a rst febrile UTI. Febrile UTI was dened as fever ($38.5 C) with no alternative source for the fever and positive urinalysis (white cell counts $105/mL) and Gram-negative rods in Gram-stained urine. Urine specimens were collected by catheter in infants or by midstream catch in older children. If sterile urine bags were used, 2 concordant consecutive urinary cultures were required. When urinalysis was positive for leukocytes and a Gram-negative strain, a blood sample was analyzed for PCT, either directly using a quantitative assay or by using a semiquantitative measurement (results given as $ or ,0.5 ng/ mL), depending on the ED. Only patients with PCT concentrations $0.5 ng/mL were included. In cases of semiquantitative PCT measurements, a quantitative measurement was done on the next working day. Patients had normal ndings on prenatal ultrasonography, no known uropathy, and no uropathy suspected after ultrasound examination at inclusion. For better visualization of inammatory lesions in the acute phase, scintigraphy should be performed as soon as possible after the onset of symptoms, ideally within 2 days4 and not exceeding 10 days.3 We decided to perform DMSA scintigraphy within the rst 8 days after inclusion. Only patients with acute lesions detected on early DMSA scintigraphy underwent follow-up and scintigraphy 6 to 8 months later. We excluded infants and children with the following characteristics:

 Aged ,1 month, prematurely born  Initial ultrasound exam revealing

obstructive uropathy, renal hypoplasia, or signs of renal abscess with a corrected age of ,1 month, or aged .36 months

 Allergy to the study drugs  Received antibiotic treatment in the

5 days before inclusion

 Patients judged as severally ill

(prolonged capillary rell; high or low blood pressure) have precluded administration of oral antibiotics

 Vomiting or diarrhea that could  Refusal from 1 or both parents  Parental misunderstanding or unsure adherence

 No Medicaid
We secondarily excluded infants and children with the following:

 Urinary culture with no bacteria,

more than 1 type of bacteria, or bacteria resistant to the study antibiotics

 Serum PCT concentration ,0.5 ng/mL

after quantitative measurement

 Normal initial DMSA scintigraphy  Recurrence of pyelonephritis before the second DMSA scintigraphy Randomization All study patients were included following the diagnosis of probable pyelonephritis at their rst consultation in the ED, before the results of urine culture and DMSA scintigraphy. Immediately after recruitment, a computergenerated code was used (clean web) to assign the patients to receive either the oral treatment or the sequential treatment. Randomization was blocked and stratied according to centers and age at inclusion (#1 year/.1 year). In the oral group, patients received cexime for 10 days, which consisted of an initial double-dose (8 mg/kg)

METHODS
Ten pediatric units collaborated in a prospective randomized trial to compare the effects of oral and sequential antibiotic regimens in children having their rst episode of APN. Patients were recruited from August 2004 to
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administered in the ED followed by 4 mg/kg twice daily. In the sequential group, patients received 50 mg/kg ceftriaxone intravenously once daily for 4 days14 followed by 4 mg/kg cexime orally twice daily for 6 days. Antibiotic therapy was started after the urine and blood samples had been analyzed and the ultrasound exam had been performed. In both groups, cexime bottles were given to the parents before discharge from the hospital. Depending on local protocols, children were admitted for the rst 12 hours then were treated as outpatients or stayed in the hospital at the discretion of the treating physician. Follow-up During the rst days of treatment, temperature was taken every 6 hours until apyrexia (,38C) persisted for .24 hours. The number of stools per day was also noted. All patients had a follow-up visit on day 4. Temperature and number of stools data were collected at this time. Patients with persistent fever at day 4 had a second PCT analysis and urinalysis performed. After the initial 10-day treatment was completed, children remained on antibiotic prophylaxis (cotrimoxazole if possible, or another antibiotic adapted to prevent bacterial resistance) until voiding cystography (VCG) could be carried out (within 1 month). Antibiotic prophylaxis was discontinued if the VCG was normal. The patients then had a follow-up by their local physician, who informed the study centers in cases of recurrent pyelonephritis. Renal DMSA Scintigraphy Patients underwent a rst DMSA scintigraphy within 8 days of inclusion. 99m Tc- DMSA renal scans were performed 3 to 4 hours after injection of a weightscaled dose of DMSA. Acute scintigraphic pyelonephritis was dened as focal or diffuse areas of decreased

DMSA uptake without evidence of cortical loss. All the renal scans were reviewed secondarily by 2 independent nuclear medicine experts, who were unaware of the treatment that had been assigned to the patients. For only those patients with abnormal acute phase scintigraphy, we scheduled another scintigraphy 6 to 8 months later to detect any renal scarring at the site of the original pyelonephritis. Statistical Methods We carried out exploratory analysis of risk of renal scarring depending on age, gender, PCT value, and vesicoureteral reux (VUR) in both treatment groups. To test the noninferiority with respect to renal scarring of the oral antibiotic therapy versus sequential therapy, the trial sample size was determined by assuming an incidence rate of renal scarring of 20% in the 2 groups and an equivalence margin of 10%. a and b risks were xed respectively to 5% and 10%. By using a 2-sided test approach, sample size was determined to be 349 subjects per group. The categorical data of the study groups were compared by using the x2 test or the Fisher exact test, where appropriate. Quantitative data were compared by using the Wilcoxon rank test. The noninferiority hypothesis of the oral treatment compared with the sequential treatment was assessed by computing the 95% condence interval (CI)

of the renal scarring incidence difference and determining whether it contained the noninferiority margin (do not reject the inferiority hypothesis) or not (reject the inferiority hypothesis and accept the noninferiority hypothesis at the 95% level). All computations were performed by using SAS software V9.2 (SAS Institute, Cary, NC).

RESULTS
The pediatric EDs participating in the trial recruited 171 children who were having their rst case of APN. Children were randomized into either the oral treatment group (cexime, n = 85) or the sequential treatment group (n = 86). The demographic and clinical characteristics of the 171 children are shown in Table 1. No signicant differences were found between the 2 groups. The mean serum PCT concentration for the oral group was not different from that of the sequential treatment group. All patients had an ultrasound exam before randomization, and no patients had signs of obstructive uropathy, renal hypoplasia, or renal abscess. Escherichia coli were isolated from the urine of 100% of the children (Table 1). Therefore, only 1 of the 161 E coli isolates was resistant to all b-lactamins. Fifty-two children who had been accepted into the study were subsequently eliminated during the rst week (Fig 1). One hundred and nineteen children, who had been correctly

TABLE 1 Demographic and Clinical Characteristics of 171 Children With Acute Pyelonephritis
Oral Treatment n = 85 Girls/boys, n (%) Age (months), mean 6 SD (range) Children 13 months of age, n Temperature at arrival (C) 6 SD (range) Time to apyrexia (h) median (Q1Q3) Procalcitonin median value (ng/mL), (Q1Q3), n = 162 Bacterial urinary pathogens (%), n = 161 VUR, n = 152 51/34 (60%) 8.9 6 6.0 (1.334.7) 10 39.3 6 0.6 (38.541.5) 24 (1242) 2.1 (1.27) n = 81 E coli (100%) n = 80 18 (23.4%) n = 77 Sequential Treatment n = 86 61/25 (71%) 10.6 6 7.6 (1.334.4) 11 39.3 6 0.6 (38.541.1) 24 (1236) 1.8 (14.6) n = 81 E coli (100%) n = 81 22 (29.3%) n = 75

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allocated to a treatment group, had an abnormal initial scintigraphy and were subjected to an intention to treat (ITT) analysis. They were scheduled for a follow-up scintigraphy 6 to 8 months later. Of these, 23 patients did not complete the study (Fig 1). In the ITT analysis, children who had an abnormal rst scintigraphy but did not undergo the follow-up scintigraphy were considered to have renal scarring. Ninetysix children completed the trial and were measured for renal scarring (per protocol analysis, PPA). Primary Outcome: Renal Scarring The 2 groups were not signicantly different from each other, either in the ITT or in the PPA (Table 2). In the ITT analysis, the incidence of renal scarring

was 41% (95% CI: 28.7%253.3%) for children in the oral treatment group and 44.8% (95% CI: 32%257.6%) in the sequential treatment group (risk difference: 23.8%; 95% CI: 221.6% to 13.9%). In the PPA, the frequency of renal scarring was 30.8% (95% CI: 18.3%2 43.3%) in the oral treatment group and 27.3% (95% CI: 14.1%240.5%) for the sequential treatment group (risk difference: +3.5%; 95% CI: 214.7% to 21.7%). In the PPA, the incidence of scarring in the both treatment groups did not differ between children aged ,1 year and children aged 1 to 3 years. The incidence of scarring also did not differ with respect to gender (Table 3). In the subgroup of 10 children ,3 months, there were no infants with renal scarring

in oral group (n = 4) and 2 infants with renal scarring (n = 6) in the sequential group. Follow-up Duration of Fever Time to apyrexia did not differ between the 2 treatment groups (median: 24 hours; Table 1). Only 2 patients had fever on day 4. Both children were excluded from the study because of violation of antibiotic protocol. The rst urinalysis of 1 child revealed an E coli strain resistant to all b-lactamins, and he received another antibiotic treatment. The second child also had gastroenteritis and received a ceftriaxone treatment longer than that of the standard study protocol.

FIGURE 1

Randomization and children ow chart.

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TABLE 2 Renal Scarring

Oral Treatment ITT (n = 119) PPA (n = 96) 25/61 (41%) (95% CI: 28.7%53.3%) 16/52 (30.8%) (95% CI: 18.3%43.3%) Standard Treatment 26/58 (44.8%) (95% CI: 32%57.6%) 12/44 (27.3%) (95% CI: 14.1% to 40.5%) Risk difference 23.8% (95% CI: 221.6% to 13.9%) Risk difference +3.5% (95% CI: 214.7% to +21.7%)

TABLE 3 Renal Scarring Depending on Age, Gender, and VUR

Oral Treatment (n = 52) Age Gender VCGa
a

Standard Treatment (n = 44) 10/30 (33.3%) 2/14 (14.3%) 7/30 (23.3%) 5/14 (35.7%) 8/33 (24.2%) 4/11 (36.4%)

Overall (n = 96) 22/67 (32.8%) 6/29 (20.7%) 17/63 (27.0%) 11/33 (33.3%) 22/73 (30.1%) 6/22 (27.3%)

,1 y $1 y Female Male Normal VUR

12/37 (32.4%) 4/15 (26.7%) 12/35 (34.3%) 4/17 (23.5%) 14/40 (35.0%) 2/11 (18.2%)

One child without renal scanning in the oral treatment group did not have VCG.

No child received any other treatment, and the 2 groups did not differed in the rate of hospitalization. Side Effects Two children did not tolerate cexime because of vomiting, and treatment was changed to parenteral therapy. One child with apparent sepsis received intravenous ceftriaxone instead of oral cexime. One child in the oral treatment group had recurrent APN 3 days after the end of the treatment. His PCT concentration was 7 ng/mL, and apyrexia occurred 24 hours after beginning the oral treatment. In his urinalysis, the E coli strain was not resistant to cexime. Serum Procalcitonin The mean serum PCT concentration was higher in children with renal scarring (n = 28; median: 3.2 ng/mL; quartiles: 1.812.1 ng/mL) than in children without scarring (n = 66; median: 1.7 ng/mL: quartiles: 14.1 ng/mL; P = .002). VUR Voiding cystography was performed for 152 children, of which 40 were found tohaveVUR(26.3%).Wefound7gradeI,18 grade II, 10 grade III, and 5 grade IV cases of VUR. In the subgroup per protocol, we
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detected VUR in 22 of 95 children (one child did not have a VCG). Regardless of VUR grade, renal scarring was similar for children with or without VUR (Table 3). Only 2 of the 5 children with grade IV VUR completed the study, and both had renal scarring at their follow-up scintigraphy.

study lacks sufcient statistical power. Three previous prospective pediatric trials have been reported that compared oral treatment to sequential treatment with respect to the incidence of renal scarring detected by DMSA scintigraphy.24 We considered only those children with rst-episode APN and an abnormal acute-phase scintigraphy in these studies. In the Hoberman et al2 study, 15 children of the 100 in the oral group with acute abnormal scintigraphy had renal scarring and 11 of 87 (12.7%) with the sequential treatment. In the Montini et al3 study, 26 of 96 (27.1%) children in the oral group and 33 of 100 in the sequential group had renal scarring. In the Neuhaus et al study,4 there were 18 of 64 children (28.1%) in the oral group and 22 of 55 (40%) in the sequential group who had denitive renal scarring. Because high serum PCT concentrations has been reported to correlate with acute renal defects detected by early DMSA scintigraphy,911 we used serum PCT concentration to identify children who were at high risk for renal involvement. Because one of our inclusion criteria was a PCT value $0.5 ng/mL, 85.4% of the patients in our study had positive acute phase scintigraphies. In the 3 previous studies,24 61.1%, 60.5%, and 63.3% of children, respectively, with febrile UTIs had abnormal acute scintigraphy. Consistent with what has been previously reported,6,10,11 we found that serum PCT concentrations were signicantly higher in children who developed scars than in those who had acute abnormalities but no denitive damage. For this reason, monitoring PCT levels in children aficted with APN could help to identify those at risk for renal complications even in the absence of a suspected or documented uropathy.6 All pathogens isolated in this study were E coli, which is usually the main pathogen isolated in UTI but not the only
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DISCUSSION
This multicenter randomized trial compared a 10-day course of oral cexime to a 4-day course of intravenous ceftriaxone treatment followed by a 6-day course of oral cexime for the treatment of 1- to 36-month-old children encountering their rst case of APN associated with renal damage, as determined by early scintigraphy. We did not nd any difference between the 2 groups in the prevalence of renal scarring detected 6 to 8 months after the infection. No currently available antibiotic therapy is able to prevent renal scarring after pyelonephritis.4 The frequencies of renal scarring in our treatment groups are comparable with those of previous trials, which reported renal scarring frequencies of 15% to 20%2,15 and 45% to 60%.3,4,6 However, it is not possible to conclude whether the oral treatment is noninferior because our

one.24 We included only UTIs with Gram-negative rods (excluding Enterococcus), children without antibiotic treatment during the 5 days before inclusion, and children with no known uropathy (limiting risk for Pseudomonas, for example). Therefore, only 1 of the 161 E coli isolates was resistant to all b-lactamins. Antimicrobial treatment with cexime is a safe choice as long as the likelihood of infection with an E coli strain that is resistant to thirdgeneration cephalosporins remains low. We chose to repeat a urinary culture at day 4 only for children who had still fever. In the 3 previous studies, the urinary culture was sterile for all children after 24 hours to 3 to 4 days of treatment,24 except for 2 children in the Montini et al study3 in whom Pseudomonas was found in the second urinary test with E coli in the rst, but even in those cases, antibiotics were continued as per protocol. In our study, blood cultures were not systematic, and thus we do not know the incidence of bacteremia. Whereas normal ultrasound results do not exclude the presence of high-grade reux, ultrasound abnormalities have been reported to correlate with reux severity.17 To include only children with a low risk of uropathy, we selected

patients with a normal prenatal ultrasonography and normal ultrasound exam at the time of APN diagnosis. This may explain why only 5 children in our study had high grade reux (grades IV or V) and why, with this small number, renal scarring did not correlate with VUR. In France, almost all units follow the 2007 Agence Franaise de Scurit Sanitaire des Produits de Sant recommendations and treat APN in children with initial parenteral treatment followed by oral antibiotic.14 For this reason, it was difcult to include a sample size large enough to achieve the necessary level of statistical signicance. In addition, 10 patients were not followed up, and 12 patients withdrew their consent. The high number of patients who dropped out of the study could reect the unwillingness of parents and their children to participate in prospective clinical trials, especially when studies last several months and include procedures that are perceived as invasive.4 Such concerns considerably reduced the number of patients in the PPA.

episodes of APN involving a Gramnegative bacteria strain in infants and children aged 1 month to 3 years who are without urological abnormalities and without clinical hemodynamic impairment. This treatment can be proposed for children with serum PCT concentrations .0.5 ng/mL who are at high risk for renal involvement, as determined by acute-phase scintigraphy, and also for children who have lower PCT concentrations, despite their low risk for acute renal involvement. Oral treatment can facilitate outpatient management of young children with APN because it reduces cost, familial disruption, and nosocomial disease exposure.

CONCLUSIONS
Our results support the use of a completely oral cexime treatment for initial

ACKNOWLEDGMENTS This study was supported by the Ministry of Health, by the Direction de la Recherche Clinique and the Unit of Clinical Research in Hospital Necker, grant PHRC no.AOM 04 105 and has the ClinicalTrials.gov identier NCT 00136656. We thank Dr Jacques Guillet (St Esprit Hospital; Agen) and Dr Eric Ouhayoun (Centre Hospitalier Universitaire Purpan; Toulouse) who provided secondary review of all renal scans. We also thank Pascale Gendron of the Clinical Research Unit, Necker Enfants Malades.

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www.pediatrics.org/cgi/content/full/121/3/ e553 16. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a rst urinary tract infection: a systematic review. Pediatrics . 2010;126(6):1084 1091 17. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a rst febrile urinary tract infection in young children. N Engl J Med. 2003;348(3): 195202

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