The n e w e ng l a n d j o u r na l of m e dic i n e
c or r e sp ondence
Antibiotic Prophylaxis and Recurrent Urinary Tract Infection
in Children
To the Editor: With regard to the article by
Craig et al. (Oct. 29 issue),1 the rationale for pro-
phylaxis is that prevention of recurrent urinary
tract infection in children lowers the risk of se-
quelae 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 anom-
alies, renal hypoplasia, or dysplasia rarely, if ever,
leads to these sequelae. Moreover, scars after py-
elonephritis are small, infrequent,2 and are prob-
ably clinically inconsequential. Since breakthrough
infection with organisms that were resistant to
trimethoprim–sulfamethoxazole occurred, it may
not be the optimal antimicrobial agent for pro-
phylaxis, especially in view of the recommenda-
tion 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 dys-
functional voiding who are predisposed to recur-
rent infection. The authors do not provide a break-
down according to sex or age for this subgroup.
How many of these children were included among
the 36 children with recurrent infection who re-
ceived 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 re-
ported.
1. Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophy-
laxis and recurrent urinary tract infection in children. N Engl J
Med 2009;361:1748-59.
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. Co-trimoxazole use restricted. Drug Ther Bull 1995;33:92-3.
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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 uri-
nary tract infections in predisposed children. Al-
though the study analyzed the increase in the num-
ber of urinary tract infections caused by bacteria
that were resistant to trimethoprim–sulfamethox-
azole, we think that the risk of selection of anti-
biotic-resistant bacteria in the intestinal commen-
sal flora and its subsequent consequences were not
adequately addressed in the article. Oral admin-
istration 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 dissem-
inate within families,2 generating an increased
risk of antibiotic-resistant infections among many
persons. Furthermore, resistance to trimethoprim–
sulfamethoxazole is strongly associated with the
this week’s letters
555 Antibiotic Prophylaxis and Recurrent Urinary
Tract Infection in Children
557 Norovirus Gastroenteritis
558 Bacterial Diarrhea
559 Phosphodiesterase Inhibitors for Pulmonary
­Hypertension
561 FDA Drug Information That Never Reaches
­Clinicians
564 Neuromuscular Symptoms and Elevated Creatine
Kinase after Statin Withdrawal
555
 The n e w e ng l a n d j o u r na l
presence of the class 1 integron,3 the major bac-
terial factor associated with pan-resistance, in-
cluding 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 world-
wide 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, France
No potential conflict of interest relevant to this letter was re-
ported.
1. Murray BE, Rensimer ER, DuPont HL. Emergence of high-
level trimethoprim resistance in fecal Escherichia coli during oral
administration of trimethoprim or trimethoprim–sulfamethox-
azole. N Engl J Med 1982;306:130-5.
2. Fornasini M, Reves RR, Murray BE, Morrow AL, Pickering LK.
Trimethoprim-resistant Escherichia coli in households of chil-
dren attending day care centers. J Infect Dis 1992;166:326-30.
3. Leverstein-van Hall MA, Blok HEM, Donders ART, Paauw A,
Fluit AC, Verhoef J. Multidrug resistance among Enterobacteria-
ceae is strongly associated with the presence of integrons and is
independent of species or isolate origin. J Infect Dis 2003;187:
251-9.
4. Partridge SR, Tsafnat G, Coiera E, Iredell JR. Gene cassettes
and cassette arrays in mobile resistance integrons. FEMS Micro-
biol Rev 2009;33:757-84.
To the Editor: We read the article by Craig et al.
with great interest, particularly since the issue of
antibiotic prophylaxis in children with vesicoureter-
al reflux and recurrent urinary tract infection re-
mains controversial.1-3 The authors report that
long-term treatment with trimethoprim–sulfa­
methoxazole was associated with a modest reduc-
tion (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
(Fig. 3 of the article). We think it would be im-
portant 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. There-
556 n engl j med 362;6  nejm.org  february 11, 2010
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
fore, we would like to ask the authors to comment
on the clinical characteristics of the children in
whom the grades of vesicoureteral reflux were un-
known.
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 re-
ported.
1. Mori R, Fitzgerald A, Williams C, Tullus K, Verrier-Jones K,
Lakhanpaul M. Antibiotic prophylaxis for children at risk of de-
veloping urinary tract infection: a systemic review. Acta Paediatr
2009;98:1781-6.
2. Pennesi M, Travan L, Peratoner L, et al. Is antibiotic prophy-
laxis in children with vesicoureteral reflux effective in prevent-
ing pyelonephritis and renal scars? A randomized, controlled
trial. Pediatrics 2008;121(6):e1489-e1494.
3. Beetz R. May we go on with antibacterial prophylaxis for
urinary tract infections? Pediatr Nephrol 2006;21:5-13.
The Authors Reply: We agree with Kallen that
urinary tract malformation, not urinary tract in-
fection, may lead to kidney disease. We are inter-
ested in the attempt to reframe our objectives. More
than 10 years ago, our primary aim and our de-
sign were to determine whether symptomatic uri-
nary tract infection is prevented with prophylactic
antibiotics. This goal remains as clinically impor-
tant now as in 1998. We are surprised at the im-
plication that the prevention of symptomatic uri-
nary 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 anony­
mous review article provides insufficient evidence
that trimethoprim–sulfamethoxazole should not
be used for this indication, particularly since no
adequately conducted trials providing valid esti-
mates 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
 correspondence
of our study. A strength of our trial was the re-
porting of infections other than urinary tract in-
fections over the follow-up period. We observed
no pattern of an increase in the incidence of ill-
ness, very few adverse drug reactions, and the use
of fewer antibiotics for other illnesses in the an-
tibiotic group. We agree that the modest benefit
of antibiotic prophylaxis needs to be considered,
as compared with other effects such as antimicro-
bial resistance. Families, clinicians, and policy-
makers would be better positioned to weigh the
benefits for individual children against the pro-
posed 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
Norovirus Gastroenteritis
To the Editor: As Glass et al. discuss in their
review article (Oct. 29 issue),1 norovirus is the
major cause of epidemic gastroenteritis and the
most common cause of diarrhea in adults. Pro-
spective studies have shown that 3 to 36% of en-
teric infections lead to a new diagnosis of the
irritable bowel syndrome,2 one of the most com-
mon gastrointestinal disorders seen in primary
care and specialist practice. A recent meta-analy-
sis of nine prospective cohort studies showed
that intestinal infection was associated with an
increase by a factor of six in the odds ratio for the
irritable bowel syndrome.3 Although pathogenic
bacteria have been identified in most studies as
etiologic factors in postinfectious cases of the
irritable bowel syndrome, recent data have indi-
cated the involvement of other infectious agents,
including viruses.2 A 2-year prospective cohort
study analyzed an outbreak of severe gastroen-
teritis attributed to a foodborne norovirus.4 At
3 months, the prevalence of postinfectious irrita-
ble bowel syndrome was significantly higher in
subjects with acute gastroenteritis than in control
subjects. Furthermore, a trend toward increased
risk was observed at 6, 12, and 24 months. Larg-
er prospective, controlled studies are awaited to
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suggest that reflux status was not an effect modi-
fier, 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 chil-
dren without reflux. Thus, if reflux was an effect
modifier, one might expect point estimates to be
between the groups with reflux and without re-
flux, 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, Australia
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
confirm that norovirus gastroenteritis could be
one of the most relevant etiologic factors in the
irritable bowel syndrome.
Cesare Cremon, M.D.
Roberto De Giorgio, M.D., Ph.D.
Giovanni Barbara, M.D.
University of Bologna
Bologna, Italy
cesare.cremon@aosp.bo.it
No potential conflict of interest relevant to this letter was re-
ported.
1. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis.
N Engl J Med 2009;361:1776-85.
2. Spiller R, Garsed K. Postinfectious irritable bowel syndrome.
Gastroenterology 2009;136:1979-88.
3. Thabane M, Kottachchi DT, Marshall JK. Systematic review
and meta-analysis: the incidence and prognosis of post-infec-
tious irritable bowel syndrome. Aliment Pharmacol Ther 2007;
26:535-44.
4. Marshall JK, Thabane M, Borgaonkar MR, James C. Postin-
fectious irritable bowel syndrome after a food-borne outbreak of
acute gastroenteritis attributed to a viral pathogen. Clin Gastro-
enterol Hepatol 2007;5:457-60.
The authors reply: Cremon et al. note that the
irritable bowel syndrome can occur in the after-
math of an episode of infectious diarrhea, often
linked to a bacterial pathogen, and ask whether
557