Published online February 11, 2008
PEDIATRICS (doi:10.1542/peds.2006-3632)
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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

a Néphrologie Pédiatrique, Hôpital des Enfants, Université Paul Sabathier, Centre Hospitalier Universitaire Purpan, Toulouse, France
b Néphrologie Pédiatrique, American Memorial Hospital, Centre Hospitalier Universitaire Reims, Beims, France
c Néphrologie Pédiatrique, Hôpital Jeanne de Flandre, Université Lille 2, Centre Hospitalier Régional Universitaire Lille, Lille, France
d Néphrologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université Montpellier I, Centre Hospitalier Universitaire Montpellier, Montpellier, France
e Néphrologie Pédiatrique, Centre Hospitalier Universitaire Saint Etienne, Saint Etienne, France
f Néphrologie Pédiatrique, Hôpital Mère Enfant, Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France
g Néphrologie Pédiatrique, Centre Hospitalier Universitaire Rennes, Rennes, France
h Néphrologie Pédiatrique, Hôpital Hautepierre, Université Louis Pasteur, Centre Hospitalier Universitaire Strasbourg, Strasbourg, France
i Médecine Nucléaire, Université Paul Sabathier, Centre Hospitalier Universitaire Purpan Toulouse, Toulouse, France
j Service de Néphrologie, Faculté de Médecine Denis Diderot, Université Paris VII, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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 pyelonephritis.

METHODS. After initial treatment with intravenous netilmicin and ceftriaxone, patients were randomly assigned to either 5 days of oral antibiotics (short intravenous treatment) or 5 days of intravenous ceftriaxone (long intravenous treatment). Inclusion criteria were age 3 months to 16 years and first acute pyelonephritis episode, defined by fever of >38.5°C, C-reactive protein level of >20 mg/L, and bacteriuria at >105/mL. All patients underwent 99m technetium-dimercaptosuccinic acid scintigraphy 6 to 9 months after inclusion. A total of 548 children were included, 48 of whom were secondarily excluded and 117 of whom were lost to follow-up or had incomplete data; therefore, 383 children were eligible, 205 of them in the short intravenous treatment group and 178 in the long intravenous treatment group.

RESULTS. At inclusion, median age was 15 months, median duration of fever was 43 hours, and median C-reactive protein level was 122 mg/L. A total of 37% (143 of 383) of patients had a vesicoureteral reflux grades 1 to 3. Patient characteristics at inclusion were similar in both groups, except for a significantly higher proportion of girls in the short intravenous treatment group. The frequency of renal scars at scintigraphy was similar in both groups. Multivariate analysis demonstrated that renal scars were significantly associated with increased renal height at initial ultrasound 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 significant risk factors for renal scars.

Key Words: children • acute pyelonephritis • antibiotics • DMSA scintigraphy

Abbreviations: APN—acute pyelonephritis • DMSA—dimercaptosuccinic acid • VUR—vesicoureteral reflux • CRP—C-reactive protein • 99mTc—99m technetium • OR—odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Acute 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 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 congenital renal dysplasia associated with urinary tract abnormalities. The prevention of renal scars by early and appropriate 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 number of prospective, randomized studies have been reported.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 followed 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 antibiotic 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 intravenous 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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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), monomicrobial positive urine culture results at >100000 colony-forming units/mL, with Escherichia coli, Proteus mirabilis, 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 uropathy; 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 Pseudomonas aeruginosa, Staphylococcus, or group D Streptococcus; 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 cystography, or APN recurrence during the period until DMSA scintigraphy.

All eligible patients were included and randomly assigned 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 intravenous netilmicin (7 mg/kg) for 2 days and ceftriaxone (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 sensitivity (short treatment group) or 5 days of intravenous ceftriaxone (long treatment group). All patients subsequently received a prophylactic trimethoprim-sulfamethoxazole 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 according 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 x 256 matrix during 5 minutes. In the youngest patients, a pinhole was used and acquisition time was prolonged 10 minutes. All biophysical centers were required to test the quality of DMSA radiopharmaceutical and to control the {gamma} camera according to the recommendations 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 heterogeneous parenchymal uptake, with or without renal shape modification, was considered as scar. During the follow-up, urinalysis was required in case of intercurrent fever.

Running Protocol
The inclusion period was from January 1999 to June 2002, and follow-up ended in June 2003. The randomization (random tables) was centralized and stratified by center, by blocks of 20 numbered sealed opaque envelopes 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 investigator and were sent to the coordination center. Data were registered in a computer base according to the french legislation (Commission nationale de l'informatique 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, number of defects, unilateral or bilateral) in December 2003 by a group of 4 independent biophysicians, without knowledge of treatment group. In case of disagreement, DMSA scans were reanalyzed in a common session.

Statistical Analysis
The sample size was calculated to demonstrate a difference of 10% in the percentage of renal scars between the 2 groups ({alpha} 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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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 (nonattendance at last visit in 87, parental refusal of DMSA scan in 30) and 48 because of secondary exclusion (recurrence of APN in 32, grade 4 or 5 VUR in 16). The proportion 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 significance (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 trimethoprim-sulfamethoxazole in 37. The initial ultrasound examination showed comparable abnormalities in both groups. The proportion of patients with VUR was also similar (Table 2). All population characteristics 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).


Figure 1
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  		FIGURE 1 Consort diagram.

 

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  		TABLE 1 Patient Characteristics at Inclusion

 

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  		TABLE 2 Initial Radiologic Findings

 

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  		TABLE 3 Results of 99mTc-DMSA Scintigraphy

 
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 significant (Table 3). Sensitivity analyses were done on different hypothesis and confirmed that long (8 days) intravenous treatment with ceftriaxone did not seem to reduce the risk for renal scars compared with short (3 days) intravenous treatment. Analysis in secondarily excluded patients gave similar results (data not shown).

Risk Factors for Renal Scars
The correlations between the presence of scars and different variables of interest are indicated in Table 4. Bivariate analysis indicated that scars were significantly more frequent in patients with VUR grades 2 and 3, in patients with CRP levels of ≥100 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.


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  		TABLE 4 Risk Factors of Renal Scars, Bivariate Analysis

 
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 after mutual adjustments for the different variables of interest, although CRP levels of ≥100 mg/L no longer appeared as a risk factor for scars (Table 2).


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  		TABLE 5 Risk Factors of Renal Scars: Multivariate Analysis

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
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 over the other. Nevertheless, sensitivity analysis showed that if 1 treatment was better than the other, then it would be the short treatment.

Second, the bacteriologic test was done on urine that was collected with sterile bags for young children, with an increased risk for false-positive bacteriuria. However, this risk was equally distributed between the 2 groups, 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 intravenous treatment group, but age, degree and duration of fever before treatment initiation, CRP, proportion of children with VUR, and VUR grades were nonsignificantly different between the 2 groups. In addition, estimations 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; therefore, patients with no initial parenchymal lesions of APN were most probably included. Nevertheless, the proportion of patients with febrile urinary tract infection without 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 administration of ceftriaxone. Four previously published randomized trials of children also did not show statistical differences 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 cefixime but included very young patients. Most of patients presented milder inflammatory conditions compared 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 other trials included a limited number of patients compared with the other studies.22,23


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  		TABLE 6 Summary of the Published Randomized Studies That Compared the Incidence of Scars at DMSA Scan According to Antibiotic Treatment Modalities

 
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 including 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 aminoglycoside in addition to ceftriaxone monotherapy. Nevertheless, 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 residual renal damage is 1 of the lowest reported. This opens the way to new prospective, randomized studies to establish the minimal treatment duration when antibiotics whose concentration remains above the minimal inhibitor concentration for a long time, such as third-generation cephalosporins, are used.33,34

The role of VUR in the development of renal scars remains controversial.35–37 However, some recent prospective studies using late DMSA scan for children with APN showed a significant association between the presence 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 intensity 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 inflammation, is associated with an increased risk for renal scars.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
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 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 Nuclear Medicine and Molecular Imaging, French Society of Pediatric Nephrology, for help and the colleagues who participated in this study: S. Decramer and C. Azéma (Hôpital des Enfants, Toulouse), B. Roussel (American Memorial 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. Palcoux (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. Ouhayoun, F. Bouissou (CHU Toulouse), F. Archambaud (Hôpital 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. Schanstra and Chantal Loirat for editorial assistance.


   FOOTNOTES
 
Accepted Aug 1, 2007.

Address correspondence to François Bouissou, MD, Néphrologie Pédiatrique, Hôpital des Enfants, TSA70034, Avenue de Grande Bretagne, 31059 Toulouse Cedex 6, France. E-mail: bouissou.f{at}chu-toulouse.fr

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


   REFERENCES
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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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Duration of IV Antibiotic Treatment for Children with Pyelonephritis
Journal Watch Pediatrics and Adolescent Medicine, March 26, 2008; 2008(326): 2 - 2.
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