Correspondence
Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children
N Engl J Med 2010; 362:555-557February 11, 2010
- Article
To the Editor:
With regard to the article by Craig et al. (Oct. 29 issue),1 the rationale for prophylaxis is that prevention of recurrent urinary tract infection in children lowers the risk of sequelae of renal scarring, such as chronic or end-stage kidney disease. However, there has been a substantial change since Craig et al. initiated their study in 1998. Recurrent urinary tract infection in children without congenital obstructing anomalies, renal hypoplasia, or dysplasia rarely, if ever, leads to these sequelae. Moreover, scars after pyelonephritis are small, infrequent,2 and are probably clinically inconsequential. Since breakthrough infection with organisms that were resistant to trimethoprim–sulfamethoxazole occurred, it may not be the optimal antimicrobial agent for prophylaxis, especially in view of the recommendation that it no longer be used.3 Craig et al. do not mention that there are children — mostly young girls between 3 and 6 years of age — with dysfunctional voiding who are predisposed to recurrent infection. The authors do not provide a breakdown according to sex or age for this subgroup. How many of these children were included among the 36 children with recurrent infection who received trimethoprim–sulfamethoxazole?
Ronald Kallen, M.D.
Northwestern University Feinberg School of Medicine, Chicago, IL
r-kallen@northwestern.edu No potential conflict of interest relevant to this letter was reported.
3 References1
Craig JC ,Simpson JM ,Williams GJ , et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 2009;361:1748-1759
Full Text | Web of Science | Medline2
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
Full Text | Web of Science | Medline3
Co-trimoxazole use restricted. Drug Ther Bull 1995;33:92-93
CrossRef | Medline
To the Editor:
Craig et al. report on a placebo-controlled trial of a long-term (12-month) regimen of low-dose trimethoprim–sulfamethoxazole that showed a small reduction in the number of urinary tract infections in predisposed children. Although the study analyzed the increase in the number of urinary tract infections caused by bacteria that were resistant to trimethoprim–sulfamethoxazole, we think that the risk of selection of antibiotic-resistant bacteria in the intestinal commensal flora and its subsequent consequences were not adequately addressed in the article. Oral administration of trimethoprim–sulfamethoxazole results in high intestinal counts of enterobacteria that are resistant to trimethoprim–sulfamethoxazole,1 and fecal carriage of such bacteria is known to disseminate within families,2 generating an increased risk of antibiotic-resistant infections among many persons. Furthermore, resistance to trimethoprim–sulfamethoxazole is strongly associated with the presence of the class 1 integron,3 the major bacterial factor associated with pan-resistance, including resistance to carbapenems.4 We believe that the modest benefit observed by the authors should be carefully weighed against these risks at a time when antibiotic resistance is a major worldwide public health priority.
David Skurnik, M.D., Ph.D.
Gerald B. Pier, Ph.D.
Harvard Medical School, Boston, MA
dskurnik@rics.bwh. harvard. edu Antoine Andremont, M.D., Ph.D.
Université Paris 7, Paris, FranceNo potential conflict of interest relevant to this letter was reported.
4 References1
Murray BE ,Rensimer ER ,DuPont HL . Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole. N Engl J Med 1982;306:130-135
Full Text | Web of Science | Medline2
Fornasini M ,Reves RR ,Murray BE ,Morrow AL ,Pickering LK . Trimethoprim-resistant Escherichia coli in households of children attending day care centers. J Infect Dis 1992;166:326-330
CrossRef | Web of Science | Medline3
Leverstein-van Hall MA ,Blok HEM ,Donders ART ,Paauw A ,Fluit AC ,Verhoef J . Multidrug resistance among Enterobacteriaceae is strongly associated with the presence of integrons and is independent of species or isolate origin. J Infect Dis 2003;187:251-259
CrossRef | Web of Science | Medline4
Partridge SR ,Tsafnat G ,Coiera E ,Iredell JR . Gene cassettes and cassette arrays in mobile resistance integrons. FEMS Microbiol Rev 2009;33:757-784
CrossRef | Web of Science | Medline
To the Editor:
We read the article by Craig et al. with great interest, particularly since the issue of antibiotic prophylaxis in children with vesicoureteral reflux and recurrent urinary tract infection remains controversial.1-3 The authors report that long-term treatment with trimethoprim–sulfamethoxazole was associated with a modest reduction (of 6 percentage points) in the number of recurrent urinary tract infections in 576 children. However, the grade of vesicoureteral reflux was unknown in 99 children (17.2%). Moreover, those children had the best response to active treatment (Figure 3 of the article). We think it would be important to know more clinical characteristics of this group (e.g., age and other risk factors such as bladder dysfunction and hypercalciuria) that may have influenced the results of this study. If most of the children had no vesicoureteral reflux, then they might have had a much better response to the active treatment, as was shown in the study. Therefore, we would like to ask the authors to comment on the clinical characteristics of the children in whom the grades of vesicoureteral reflux were unknown.
Agnieszka Szmigielska, M.D.
Grazyna Krzemien, M.D., Ph.D.
Maria Roszkowska-Blaim, M.D., Ph.D.
Medical University of Warsaw, Warsaw, Poland
aszmig@yahoo.com No potential conflict of interest relevant to this letter was reported.
3 References1
Mori R ,Fitzgerald A ,Williams C ,Tullus K ,Verrier-Jones K ,Lakhanpaul M . Antibiotic prophylaxis for children at risk of developing urinary tract infection: a systemic review. Acta Paediatr 2009;98:1781-1786
CrossRef | Web of Science | Medline2
Pennesi M ,Travan L ,Peratoner L , et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121:e1489-e1494
CrossRef | Web of Science | Medline3
Beetz R . May we go on with antibacterial prophylaxis for urinary tract infections? Pediatr Nephrol 2006;21:5-13
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Kallen that urinary tract malformation, not urinary tract infection, may lead to kidney disease. We are interested in the attempt to reframe our objectives. More than 10 years ago, our primary aim and our design were to determine whether symptomatic urinary tract infection is prevented with prophylactic antibiotics. This goal remains as clinically important now as in 1998. We are surprised at the implication that the prevention of symptomatic urinary tract infection is not a worthwhile outcome from the perspective of the child and family. In our experience, families want to prevent further urinary tract infections. A reference to one anonymous review article provides insufficient evidence that trimethoprim–sulfamethoxazole should not be used for this indication, particularly since no adequately conducted trials providing valid estimates of benefits and harms have been reported. As we reported in Table 1 of our article, most children enrolled in the study were younger than 3 years of age. There is a limit to the number of post hoc subgroup analyses that should be done to satisfy every reader. The overall study result is the most robust and was remarkably consistent across the subgroups reported.
We are grateful to Skurnik et al. for raising the broader health impact of antibiotic resistance. An analysis of intestinal flora was beyond the scope of our study. A strength of our trial was the reporting of infections other than urinary tract infections over the follow-up period. We observed no pattern of an increase in the incidence of illness, very few adverse drug reactions, and the use of fewer antibiotics for other illnesses in the antibiotic group. We agree that the modest benefit of antibiotic prophylaxis needs to be considered, as compared with other effects such as antimicrobial resistance. Families, clinicians, and policymakers would be better positioned to weigh the benefits for individual children against the proposed harmful effects of increased resistance if researchers obtained reliable, quantified estimates of the clinically important sequelae of increased resistance.
Szmigielska and colleagues should be cautious about overinterpretation of Figure 3. These data suggest that reflux status was not an effect modifier, although we acknowledge that our study was not powered to detect interactions. The group of patients in whom the reflux grade was unknown probably included children with reflux and children without reflux. Thus, if reflux was an effect modifier, one might expect point estimates to be between the groups with reflux and without reflux, but we did not observe this. Indeed, one of the key findings of our study is that the treatment effect was very consistent across subgroups.
Jonathan C. Craig, M.B., Ch.B., Ph.D.
Gabrielle J. Williams, Ph.D., M.P.H.
Judy M. Simpson, Ph.D.
University of Sydney, Sydney, NSW, AustraliaSince publication of their article, the authors report no further potential conflict of interest.
- Citing Articles (1)
Citing Articles
1
Grace S. Phillips, Angelisa Paladin. (2012) Essentials of Genitourinary Disorders in Children: Imaging Evaluation. Seminars in Roentgenology 47:1, 56-65
CrossRef
