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Parenteral or oral antibiotics in childhood pyelonephritis: Does the debate still continue
- Ahmet Karadag, Zekai Avci, Alparslan Tonbul, Ferhat Catal, Ajla Wasti (18 July 2007)
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Response to Montini Article
- Alejandro Hoberman, Ellen R. Wald (12 October 2007)
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Response to Montini article - Is this study valid?
- V Ganesan (26 November 2007)
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Re: Response to Montini Article
- Giovanni Montini, and Pietro Zucchetta, Consultant in Nuclear Medicine, Azienda Ospedaliera of Padua, Italy (9 December 2007)
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Re: Response to Montini article - Is this study valid?
- Giovanni Montini (9 December 2007)
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Ahmet Karadag, MD UCLA Harbor, Department of Pediatrics 1124 West Carson St., RB1, Torrance, CA 90502, USA, Zekai Avci, Alparslan Tonbul, Ferhat Catal, Ajla Wasti
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We have taken an interest in a recently published article in your journal by Montini et al. Although we completely agree with the conclusion that treatment with oral antibiotics is as effective as parenteral treatment in the management of the first episode of clinical pyelonephritis in children, we would like to emphasize a different angle of this subject. P>As has previously been established, use of some parenteral antibiotics in the management of childhood pyelonephritis has been shown to have side effects on the urinary tract (1,2). Specifically, parenteral ceftriaxone, which is the most commonly used drug in the treatment of childhood pyelonephritis, has been linked to cases of nephrolithiasis (1,2). Our studies showed that children taking a seven day course of normal- or high-dose ceftriaxone, may develop small sized asymptomatic renal stones (1). In ceftriaxone-treated patients, the overall incidence of nephrolithiasis in our study was 7.8% (1). Montini et al's article documents the use of a ceftriaxone dose of 50 mg/kg daily (1). We would like to bring to light, that according to our studies even this small a dose carries with it the risk of kidney stone formation. We believe that when efficacy and side effects of parenteral vs oral drugs have been considered, oral treatment seems to be a better choice in children with pyelonephritis. References 1. Avci Z, Koktener A, Uras N, Catal F, Karadag A, Tekin O et al. Nephrolithiasis associated with ceftriaxone therapy: a prospective study in 51 children. Arch Dis Child 2004;89:1069-72. 2. Avci Z, Karadag A, Odemis E, Catal F. Re: Pediatric ceftriaxone nephrolithiasis. J Urol 2005;174:1153 Competing interests: None declared |
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Alejandro Hoberman, Professor of Pediatrics Children's Hospital of Pittsburgh, 15213, Ellen R. Wald
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We were pleased to read the study by Montini and co-workers which has further substantiated our study regarding the effectiveness of using oral antimicrobials for the management of acute pyelonephritis in children.1 We congratulate them on enrolling this large cohort of children. The difference in proportion of girls vs boys among children in the two studies may well relate to the frequency of circumcision in the two populations. Our population studied in the US included relatively few uncircumcised boys; accordingly, the rate of UTI among boys in general will be reduced. The rate of circumcision in the Italian study is not cited. Conway et al evaluated electronic health record data from a network of 27 primary care practices; 543 (89%) of the 611 children aged 6 years or younger diagnosed with an initial UTI were female.2 The rate of reflux noted in our study (40%) is quite consistent with the results of numerous other investigations.3, 4 The differences in rates of scarring are quite interesting. Because we studied children less than 2 years of age, the threshold for evaluation for the presence of UTI may have been lower resulting in earlier diagnosis and treatment and therefore less scarring. This is perhaps reflected in the shorter time to defervescence and the lower rate of scarring – which is also consistent with more recent studies.5 Additional unanswered questions we have regarding the Montini study include: (1) the timing of entry is not clear: were children enrolled after the first sample of urine or after the second confirmatory urine was obtained?, (2) the assumption that children with initial negative DMSA scans had no reinfections during the ensuing year in order to assume that a negative initial scan results in a negative follow-up scan (88 and 89 children in the oral and parenteral treatment groups, respectively); (3) a relatively large proportion of children (20.3%) lost to follow-up, and (4) with regard to interpretation of DMSA renal scans, (a) whether any interobserver agreement was measured in preparation for or during the trial, (b) whether any standardization of interpretations by regions or extent, other than definitions of acute pyelonephritis and renal scarring were utilized. References: 1. Montini G, Toffolo A, Zucchetta P, et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. Br Med J 2007; 335:386. 2. Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. Jama 2007;298(2):179-86. 3. Downs SM. Technical report: urinary tract infections in febrile infants and young children. The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement. Pediatrics 1999;103(4):e54. 4. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103(4 Pt 1):843-52. 5. Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006;117(3):626-32. Competing interests: None declared |
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V Ganesan, Consultant Paediatrician City Hospital Birmingham B18 7QH UK
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This multicentre RCT evaluating exclusive use of oral antibiotics for treatment of pyelonephritis in young children recently drew my attention. I very much appreciate the enormous amount of time and effort spent on conducting this trial and writing this paper. However I have some fundamental doubts about the validity of this paper. 1] Case definition (UTI)- In this study urine was collected from febrile children using "sterile" bags and screened with dipstick for 1+ leucocytes before sending for culture. Published information suggests that around 340 children were aged <12 months. It is well recognised that urine collection method determines the diagnostic validity of the urine tests. Data from a Canadian study (McGillivray et al in J Pediatr. 2005 Oct;147(4):451-6) demonstrated that specificity was consistently lower for bag specimens (0.62) compared to catheter specimens (0.92). Although two urine specimens were obtained and colony counts >100 000 of single organism was used, it still leaves room for uncertainty about the diagnosis of UTI in these febrile children. 2] Case definition (Pyelonephritis) - Authors acknowledge that those with negative DMSA scan result at entry were considered to have a "febrile UTI in the absence of acute pyelonephritis". So this group (44.6% of those randomised n=224) is not relevant to the title of this paper at all as it suggests to deal with treatment for "pyelonephritis". This will affect the power of this study significantly. 3] Drop out rates - Authors acknowledge that 20.3% patients (n=102) were lost to follow-up after completion of antibiotic treatment. This is further exaggerated in the subgroup relevant to the title of the study (Table 3). Drop out rate in this subgroup is as high as 30% (primary outcome of DMSA evaluation at 12 months is available only for 196 out of 278) 4] Conclusion - Although it is designed as a non-inferiority trial, exploratory subgroup analysis (Table 3) suggests that 95% confidence interval around risk difference ranges upto 18.7% in favour of exclusive oral treatment group. In other words, in febrile children with pyelonephritis exclusive oral antibiotic treatment is 19% less likely to be associated with renal scar at 12 months compared to treatment with initial 3 day IV antibiotics followed by oral antibiotics. This somehow seems to imply that exclusive oral antibiotic treatment is better which seems biologically implausible. 5] Relevance to UK context - It is worrying that recently published NICE guideline on UTI in children rests on such articles that seem impressive on the first look but have doubtful validity on close scrutiny. Competing interests: None declared |
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Giovanni Montini, Consultant in Pediatric Nephrology Departement of Pediatrics, Azienda Ospedaliera Of Padua, 35128, Padua, Italy, and Pietro Zucchetta, Consultant in Nuclear Medicine, Azienda Ospedaliera of Padua, Italy
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We thank Hoberman and Wald for their comments on our study. We agree that the frequency of circumcision in the Italian and American population could account for the difference of girls vs boys in the two studies, as Italian boys are almost all uncircumcised. We also agree that the difference in rates of scarring is quite interesting. Age cannot be accounted to explain such a difference. A more detailed analysis of our data has shown that the risk of scarring is not related to the age of the child; furthermore almost 90% of our patients were below 2 years of age. The longer time to defervescence, in our study, could be an explanation to the higher rate of scarring, as both of them were longer in our study for either the exclusive oral treatment and the initial 3 day parenteral antibiotic regime, followed by oral treatment. We do not have an explanation for differences in the time to defervescence in the 2 studies. Unanswered questions: 1) Children were enrolled after the second confirmatory urine was obtained. 2) It was those patients ultimately confirmed to have pyelonephritis on scintigraphy that were of interest, as they were the ones at risk of subsequent kidney damage. In Hoberman's paper none of the children who had normal acute DMSA scans developed scarring in follow-up; this was one of the reasons we did not subject our patients to a repeat DMSA, when the acute study was normal, as this would have involved additional unwarranted radiation. 3) We have stated in the discussion that the drop out rate of 20% is a weakness of our study. This is expected in a study of this nature, as parents decline the follow-up study because of concerns regarding its invasive nature and the concomitant radiation dose in a child who has no further infections. The dropout rate was similar in both treatment groups; therefore it is unlikely to have affected the results. 4) a. Interobserver agreement was evaluated before and after the completion of the trial. The resulting kappa statistic was respectively 0.83 and 0.84. Furthermore, it is worth mentioning, that our centre recently participated in a multicentre trial on DMSA evaluation. The results of the study have been submitted for publication, but it has been anticipated at a recent meeting that the median agreement was 94% and the agreement was less than 0.8 in only 11% of cases (Personal communication, D. De Palma, Paediatric Committee of the European Association of Nuclear Medicine). b. Data on semi-quantitative analysis of renal involvement were beyond the scope of the present paper. This aspect will be considered for a specific study. Competing interests: None declared |
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Giovanni Montini, Consultant in Pediatric Nephrology Departement of Pediatrics, Azienda Ospedaliera of Padua, 35128 Padua, Italy
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Of course, it is! I appreciate the time Dr Ganesan spent analysing our paper. This study is not only valid but also useful to the children with a febrile urinary tract infection. The scientific reliability of the study is high, because of both the large numbers included and a good study design. In our study, children were enrolled prospectively, when there was a high index of suspicion of pyelonephritis based on the clinical presentation, i.e. fever with an active urine sediment and subsequent positive urine culture, with elevated indices of inflammation. This situation identifies clinical pyelonephritis. Of course there is a difference between “clinical” pyelonephritis and “confirmed pyelonephritis” based upon the Tc DMSA findings. Physicians and paediatricians deal with and treat clinical pyelonephritis. A DMSA scan is rarely performed during the acute phase of the disease in the routine setting. It would be unconscionable to await up to several days for scintigraphic evidence of PN prior to treating a febrile children. 1) Case definition (UTI)- We agree with Dr Ganesan that urine collected using sterile bags to perform urinalysis and urine culture, has a higher possibility of contamination. This increased risk of contamination represents the rationale to collect the urine twice: two consecutive concordant urinalyses and culture minimise the risk of contamination and false positive tests. Furthermore, urine collection was performed by experienced nurses, following a standardised, carefully prepared protocol, which required changing the bag every 20 to 30 minutes. Two previous similar studies (1-2) have found the same proportion of children with pyelonephritis confirmed by scintigraphy (63.5 and 61 % respectively) than in our study (63.5%). In those trials the diagnosis of UTI was based on urines from either a catheterised or midstream, clean void urine sample in the first study or from a specimen obtained by catheter in the second study. This indicates that our data are as valid as those obtained with what is seen as the gold standard. 2) Case definition (Pyelonephritis) - As previously commented, in the routine setting not all febrile urinary tract infections prove to be acute pyelonephritis, but are assumed so for the purposes of treatment. Treatment is commenced usually when only the result of a urinalysis is available, the urine culture coming later. We aimed to evaluate what happens in a routine clinical scenario. Therefore the group of children with "febrile UTI in the absence of acute pyelonephritis" is very relevant to the title of this paper. An exploratory subgroup analysis of primary and secondary outcomes in the group of children with pyelonephritis confirmed by scintigraphy was then performed, to evaluate the selected patients with proven pyelonephritis as this same issue was unresolved in the Hoberman paper (3). 3) Drop out rates - The drop out rate is 20.3 %. This is expected in a study of this nature, as parents decline the follow-up study because of concerns regarding its invasive nature and the concomitant radiation dose in a child with no other relapses of infections. We had stated this point as a weakness of our study, in the discussion. As the drop-out rate was similar in both treatment groups, it is unlikely to have affected the results. 4) Conclusion - Exclusive oral treatment, even if biologically implausible, is non-inferior to initial 3 day parenteral antibiotics followed by oral treatment also for the exploratory subgroup analysis. 5) Relevance to UK context - if guidelines do not rely upon the only two randomised controlled studies so far published, upon what do they have to rely? The lively debate and the number of recent papers on the argument confirm the interest of the medical community for this clinical issue. References. 1. Pecile P, Miorin E, Romanello C, Falleti E, Valent F, Giacomuzzi F, Tenore A. Procalcitonin: a marker of severity of acute pyelonephritis among children. Pediatrics. 2004 Aug;114(2):e249-54. 2. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med. 2003;348:195-202. 3. Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M, Kearney DH, Reynolds EA, Ruley J, Janosky JE. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999 Jul;104:79-86. Competing interests: None declared |
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