To confirm whether oral antibiotic treatment is as efficacious as sequential intravenous/oral antibiotic treatment in the prevention of renal scarring in children with acute pyelonephritis and scintigraphy-documented acute lesions.
In a prospective multicenter trial, children aged 1 to 36 months with their first 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 cefixime for 10 days or intravenous ceftriaxone for 4 days followed by oral cefixime for 6 days. Patients with acute renal lesions detected on early dimercaptosuccinic acid scintigraphy underwent a follow-up scintigraphy 6 to 8 months later.
The study included 171 infants and children. There were no significant 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 follow-up 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.
Although this trial does not statistically demonstrate the noninferiority of oral treatment compared with the sequential treatment, our study confirmed 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.
Kate Hodgson1, Sally Campbell1, Francesca Orsini2, Suzanne Vidmar2, Thomas G Connell 1,2
1 Department of General Medicine, Royal Children's Hospital Melbourne, Victoria, Australia 2 Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne
The use of potentially less intensive treatment regimens for acute pyelonephritis is topical in paediatrics(1). We read with interest the recent paper by Bocquet et al comparing oral to sequential IV/oral antibiotics for the treatment of acute pyelonephritis in infants and children (2). The authors should be commended for attempting a multi- centre randomized controlled trial (RCT) to complement existing evidence supporting less intensive treatment approaches in children(1). Nevertheless, we have significant concerns regarding the study methodology, analysis and interpretation and feel the authors have significantly overstated their conclusions. We therefore believe cautious interpretation of the study finding is warranted.
In this study, children with their first febrile urinary tract infection (UTI) with abnormalities on DMSA were randomised to receive 10 days of oral cefixime (PO) or sequential intravenous cefotaxime (4 days) followed by oral cefixime (6 days) (IV/PO arm). The primary endpoint in the study was the presence of renal scarring on follow-up DMSA testing up to eight months later. Based on the observation that the proportion of patients in each group with renal scarring was similar in both groups, the authors conclude that their study 'supports the use of an oral antibiotic treatment of primary episodes of acute pyelonephritis in infants and young children'. We contend that the authors' conclusions are invalid as a result of several methodological limitations.
Assuming an incidence of renal scarring approaching one in five (20%) in their cohort, the authors calculated the required sample size based on an equivalence or non-inferiority margin of 10% between the treatment arms. However, the study was significantly underpowered to detect a difference, even if one truly existed, between the oral or sequential IV/PO antibiotic treatment arms for the primary outcome. In the intention to treat analysis, 14 patients were lost to follow up in the IV/PO arm compared to nine in the PO arm, all of which were assumed to have renal scarring, skewing the results in favour of the exclusive PO arm. In addition, from the data provided in table 2 of the manuscript it can be seen that the 95% CI for the difference in renal scarring between the two groups in the intention to treat and per protocol analysis extends well beyond the 10% set by the authors to define their equivalence or non- inferiority margin. In fact, the 95% CI in the per protocol analysis suggests that the proportion of renal scarring could be as much as 21.7% higher using oral compared to sequential IV/PO treatment. This contradicts the authors' conclusion that their results support the use of PO treatment only.
The relatively rigorous inclusion criteria may have potentially explained the poor recruitment over four-year study period and question the generalizability of the study finding to patients presenting with fever and UTI in whom results of ultrasound and DMSA investigations are not readily available or routinely undertaken. The authors do not provide details regarding the time to treatment from randomization and we presume that no treatment was unnecessarily delayed pending the results of a renal ultrasound. Information regarding the results of blood culture testing would also have been informative and may have influenced treatment selection. Furthermore, we question the requirement for VCUG in all patients as several studies have now shown that high-grade reflux can be reliably detected with US in most instances (3-5).
Despite the shortcomings to the study by Boquet and colleagues that preclude definitive conclusions, the study adds to the increasing number that have investigated the use of less intensive treatment regimens for the treatment of acute pyelonephritis in children(1). We eagerly await the results of future adequately powered prospective randomised controlled studies to provide the definitive evidence needed that will lead to a change in current clinical management.
References
1. Hodson EM, Willis NS, Craig JC. Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2007(4):CD003772. Epub 2007/10/19. 2. Bocquet N, Sergent Alaoui A, Jais JP, Gajdos V, Guigonis V, Lacour B, et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012;129(2):e269-75. Epub 2012/02/01. 3. Ismaili K, Wissing KM, Lolin K, Le PQ, Christophe C, Lepage P, et al. Characteristics of first urinary tract infection with fever in children: a prospective clinical and imaging study. The Pediatric infectious disease journal. 2011;30(5):371-4. Epub 2011/04/20. 4. South M. Radiological investigations following urinary tract infection: changes in Australian practice. Archives of disease in childhood. 2009;94(12):927-30. Epub 2009/08/13. 5. Schroeder AR, Abidari JM, Kirpekar R, Hamilton JR, Kang YS, Tran V, et al. Impact of a more restrictive approach to urinary tract imaging after febrile urinary tract infection. Archives of pediatrics & adolescent medicine. 2011;165(11):1027-32. Epub 2011/11/09.
Conflict of Interest:
None declared
We read with interest the article 'Randomized Trial of Oral Versus Sequential IV/Oral Antibiotic for Acute Pyelonephritis in Children' by Bocquet et al. The authors demonstrated no statistical difference between sequential intravenous/oral antibiotic treatment and oral treatment alone for primary episodes of acute pyelonephritis in children aged 1-36 months. They supported the use of oral antibiotics, which could be given without requiring admission to hospital. We note that more than one third of children did not receive the allocated intervention and there were also protocol violations. This is a substantial number to be unaccounted. However, we do know that one child with apparent sepsis was treated with intravenous instead of oral antibiotics, suggesting that the treating clinician did not consider the study protocol to be safe for this child. The conclusions generalise the findings beyond the cohort of children with E. Coli infections to include any gram negative bacteria. However, more importantly, the substantial deviations from the protocol raise significant concerns regarding the safety of following the recommendations without the overriding exercise of clinical judgement. Keeping both of these constraints in mind, we suggest to the readers that the protocol recommended here be considered cautiously before implementing in clinical management.
Conflict of Interest:
None declared