Correspondence *Division of Pediatric Nephrology, University of California, San Diego, 9500 Gilman Drive, MC 0634, La Jolla, CA 92093-0634, USA

Email romak@ucsd.edu

Original article

Montini G et al. (2007) Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ 335: 386   PubMed

Synopsis

Background

Guidelines for the management of acute pyelonephritis in children currently recommend that oral antibiotic therapy is preceded by parenteral treatment with a third-generation cephalosporin.

Objective

To compare the efficacy of the standard antibiotic regimen for children who have acute pyelonephritis (parenteral administration followed by oral treatment) with that of an oral-only regimen.

Design

This multicenter, open-label, noninferiority trial took place at pediatric units in Italy between June 2000 and July 2005. Children were eligible to enter the study if they had a first episode of acute pyelonephritis (as indicated by urinalysis and urine culture) and two of the following characteristics: fever 38 °C, inflammatory indices (raised erythrocyte sedimentation rate or C-reactive protein level) in the first 48 h of presentation, and an elevated neutrophil count. Schwartz-estimated creatinine clearance 70 ml/min/1.73 m² and urological abnormalities were exclusion criteria.

Intervention

After stratification by age and gender, children were randomized to receive either oral co-amoxiclav (amoxicillin plus clavulanic acid) 50 mg/kg/day (in 3 doses) for 10 days, or parenteral ceftriaxone 50 mg/kg/day (in 1 dose) for 3 days followed by oral co-amoxiclav 50 mg/kg/day (in 3 doses) for 7 days. Dimercaptosuccinic acid (DMSA) scintigraphy was scheduled to occur no more than 10 days after initiation of antibiotic treatment and was repeated 1 year later only if the findings were positive for acute pyelonephritis; a negative result on initial scintigraphy was considered predictive of a negative result at 1 year.

Outcome measure

The rate of renal scarring, as detected by DMSA scintigraphy at 1 year, was the primary end point.

Results

A total of 502 children were enrolled (age range 1–99 months), of whom 244 were randomized to receive oral antibiotic treatment only and 258 were randomized to receive standard treatment. Baseline demographic and clinical characteristics, and the proportions of patients who were lost to follow-up (total n = 102), were similar in the two groups. Among the 400 children who completed the trial, there was no significant difference in the rate of renal scarring at 1 year between those who received oral antibiotics only and those who received initial parenteral antibiotic treatment (13.7% vs 17.7% [27/197 vs 36/203]; risk difference -4.0%, 95% CI -11.1% to 3.1%). Oral-only treatment remained noninferior to standard treatment with regard to the rate of renal scarring in the subset of 196 children in whom diagnosis of pyelonephritis was confirmed by initial scintigraphy (27.8% vs 33.0% [26/96 vs 33/100]; risk difference -5.8%, 95% CI -18.7% to 6.9%). Minor adverse effects were seen in 15 children who initially received co-amoxiclav treatment (10 of whom required a change of therapy), and in 3 children who received initial ceftriaxone treatment (none requiring a change of therapy).

Conclusion

Oral-only antibiotic treatment for a first episode of acute pyelonephritis is acceptable in children without urological abnormalities.

Commentary

Following a dramatic reduction in the prevalence of infections caused by Haemophilus influenzae and Streptococcus pneumoniae as a result of effective conjugate vaccines,¹ urinary tract infection (UTI) is now the most common serious bacterial infection of infancy and early childhood. Pyelonephritis can have severe acute complications, such as shock and septicemia, as well as long-term adverse outcomes resulting from renal parenchymal scarring, such as hypertension and chronic kidney disease. Current published guidelines for the management of a first episode of acute pyelonephritis in children recommend inpatient intravenous antibiotic therapy, followed by oral therapy, for a combined duration of 7–14 days.²

Montini et al. conducted a randomized, nonblinded, controlled noninferiority trial in children with a first episode of acute pyelonephritis. They showed that oral co-amoxiclav for 10 days was as efficacious (in terms of preventing renal scarring on DMSA scan at the end of a 1-year follow-up period) as treatment with parenteral ceftriaxone for 3 days followed by oral co-amoxiclav for 7 days.

Previously, Hoberman et al.³ compared the effects of an oral third-generation cephalosporin (cefixime) given for 14 days with those of a regimen comprising intravenous cefotaxime therapy for 3 days followed by oral cefixime therapy for 10 days for the treatment of infants with acute pyelonephritis. They showed that there were no differences between the regimens in terms of the timing or likelihood of resolution of acute symptoms, the rate of UTI recurrence, or the frequency of renal scarring on DMSA scans at 6-month follow-up. The estimated average cost of oral-only antibiotic treatment was less than half that of intravenous plus oral treatment. The total healthcare savings that could be obtained with widespread use of oral therapy alone would be tremendous considering the prevalence of UTIs.

We must, however, consider several caveats before recommending outpatient oral antibiotic treatment of all children with acute pyelonephritis. Montini et al. admitted all patients to hospital and monitored them carefully for at least 3 days; they did not compare inpatient and outpatient treatment. Unless the child's parents are reliable, vigilant, and willing to work very closely with the primary care physician, a totally outpatient approach to the treatment of acute pyelonephritis, using oral antibiotics alone, might not be warranted. Furthermore, more than one-third of the patients studied by Montini and co-workers were under the age of 6 months. The difficulty of recognizing urosepsis in the outpatient setting, the rapid deterioration of urosepsis and the risk of fluid and electrolyte disorders could be good arguments for excluding this age group from outpatient-only treatment.

Montini et al. aimed to exclude children with urological abnormalities, identified on the basis of prenatal ultrasonographic findings, but reliance on prenatal screening for detection of such abnormalities cannot be recommended in the routine management of a first episode of pyelonephritis. In the study of Hoberman et al., post hoc analysis raised the possibility that, among children with grade III–V vesicoureteric reflux, renal scarring at 6 months might occur more frequently after oral antibiotic treatment than after intravenous plus oral antibiotic therapy. No such analysis was carried out in Montini's study. Additional data are needed to determine the efficacy of oral antibiotics alone for acute pyelonephritis in children with high-grade reflux. Further studies are also needed to evaluate wide-spectrum oral antibiotics other than those administered by Montini et al., particularly as endemic community bacterial resistance is emerging from the widespread use of antibiotics such as co-amoxiclav in several parts of the world.

Acknowledgments

The synopsis was written by Chloë Harman, Associate Editor, Nature Clinical Practice.

References

1. Wald E (2004) Urinary tract infections in infants and children: a comprehensive overview. Curr Opin Pediatr 16: 85–88 | Article | PubMed |
2. Bloomfield P et al. Antibiotics for acute pyelonephritis in children. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD003772.pub2 doi: 10.1002/14651858.CD003772.pub2 | Article |
3. Hoberman A et al. (1999) Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 104: 79–86 | Article | PubMed | ChemPort |

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Subject areas under which this article appears: Pediatric nephrology