ORIGINAL CONTRIBUTION
Recurrent Urinary Tract Infections in Children
Risk Factors and Association With Prophylactic Antimicrobials
Patrick H. Conway, MD, MSc
Avital Cnaan, PhD
Theoklis Zaoutis, MD, MSCE
Brandon V. Henry, BS
Robert W. Grundmeier, MD
Ron Keren, MD, MPH
E
STIMATES OF CUMULATIVE INCI-
dence of urinary tract infec-
tion (UTI) in children younger
than 6 years (3%-7% in girls,
1%-2% in boys) suggest that 70 000 to
180 000 of the annual US birth cohort
will have experienced a UTI by age 6
years.1-3 Very few studies have evalu-
ated the risk of recurrent UTI, and none
have studied children with UTI iden-
tified and managed in a primary care
setting. Most prior studies have esti-
mated 6- to 12-month UTI recurrence
rates of 20% to 48%, but these esti-
mates may be exaggerated because they
typically were derived from referral
populations with multiple previous
UTIs or from trials in which children
were catheterized without symptoms,
in which case positive culture results
may represent asymptomatic bacteri-
uria.1,4-9
The 1999 American Academy of Pe-
diatrics practice guideline for manage-
ment of children after first UTI recom-
mends an imaging study to evaluate for
the presence and degree of vesicoure-
teral reflux (VUR),10 a condition pre-
sent in approximately 30% to 40% of
children with UTI.11 If the child has
VUR, daily antimicrobial prophylaxis
is recommended to prevent recurrent
UTIs.11,12 The basis for this VUR screen-
©2007 American Medical Association. All rights reserved.
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Context The evidence regarding risk factors for recurrent urinary tract infection (UTI)
and the risks and benefits of antimicrobial prophylaxis in children is scant.
Objectives To identify risk factors for recurrent UTI in a pediatric primary care co-
hort, to determine the association between antimicrobial prophylaxis and recurrent
UTI, and to identify the risk factors for resistance among recurrent UTIs.
Design, Patients, and Setting From a network of 27 primary care pediatric prac-
tices in urban, suburban, and semirural areas spanning 3 states, a cohort of children
aged 6 years or younger who were diagnosed with first UTI between July 1, 2001,
and May 31, 2006, was assembled. Time-to-event analysis was used to determine risk
factors for recurrent UTI and the association between antimicrobial prophylaxis and
recurrent UTI, and a nested case-control study was performed among children with
recurrent UTI to identify risk factors for resistant infections.
Main Outcome Measures Time to recurrent UTI and antimicrobial resistance of
recurrent UTI pathogens.
Results Among 74 974 children in the network, 611 (0.007 per person-year) had a
first UTI and 83 (0.12 per person-year after first UTI) had a recurrent UTI. In multi-
variable Cox time-to-event models, factors associated with increased risk of recurrent
UTI included white race (0.17 per person-year; hazard ratio [HR], 1.97; 95% confi-
dence interval [CI], 1.22-3.16), age 3 to 4 years (0.22 per person-year; HR, 2.75; 95%
CI, 1.37-5.51), age 4 to 5 years (0.19 per person-year; HR, 2.47; 95% CI, 1.19-5.12),
and grade 4 to 5 vesicoureteral reflux (0.60 per person-year; HR, 4.38; 95% CI, 1.26-
15.29). Sex and grade 1 to 3 vesicoureteral reflux were not associated with risk of
recurrence. Antimicrobial prophylaxis was not associated with decreased risk of re-
current UTI (HR, 1.01; 95% CI, 0.50-2.02), even after adjusting for propensity to re-
ceive prophylaxis, but was a risk factor for antibimicrobial resistance among children
with recurrent UTI (HR, 7.50; 95% CI, 1.60-35.17).
Conclusion Among the children in this study, antimicrobial prophylaxis was not as-
sociated with decreased risk of recurrent UTI, but was associated with increased risk
of resistant infections.
JAMA. 2007;298(2):179-186 www.jama.com
ing and treatment strategy is a theo- scarring.13-15 However, there is a pau-
retical model that links VUR to an in- city of evidence for this model,9 and re-
creased risk of recurrent UTI and renal cent small clinical trials evaluating the
Author Affiliations: Robert Wood Johnson Founda- Informatics (Dr Grundmeier), Children’s Hospital of Phila-
tion Clinical Scholars Program (Dr Conway), Leonard delphia; and Center for Health Care Quality and Divi-
Davis Institute of Health Economics (Drs Conway, Zaou- sion of General Pediatrics, Cincinnati Children’s Hospi-
tis, and Keren), Center for Clinical Epidemiology and Bio- tal Medical Center, Cincinnati, Ohio (Dr Conway).
statistics (Drs Conway, Cnaan, Zaoutis, and Keren), and Corresponding Author: Patrick H. Conway, MD, MSc,
School of Medicine (Mr Henry), University of Pennsyl- Robert Wood Johnson Clinical Scholars Program, Uni-
vania, Philadelphia; Division of General Pediatrics (Drs versity of Pennsylvania, 423 Guardian Dr, Blockley Hall
Conway, Zaoutis, and Keren), Division of Biostatistics 1303A, Philadelphia, PA 19104 (pconway2@mail.med
and Epidemiology (Dr Cnaan), and Center for Biomedical .upenn.edu).
(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 179
 RECURRENT URINARY TRACT INFECTIONS IN CHILDREN
Figure. Primary Care Cohort
74 974 Children aged 6 years
or younger with at least
2 clinic visits
775 With record of urinary
tract infection
164 Excluded
91 Previous UTI
55 Observation time <24 d
17 Comorbid conditions
1 UTI diagnosed by
bag specimen
611 With first UTI included
in analysis
83 With recurrent UTI
UTI indicates urinary tract infection.
efficacy of prophylaxis have demon-
strated no protective effect for prevent-
ing recurrent UTI and renal scar-
ring.5,16 Moreover, concerns have been
raised about the potential harm of an-
timicrobial prophylaxis because of its
potential to breed resistant organisms
that can cause recurrent UTIs.17
Given the limited information
regarding risk factors for recurrent
UTI and the risks and benefits of anti-
microbial prophylaxis, we sought to
(1) identify risk factors for recurrent
UTI in a pediatric primary care
cohort, (2) examine the association
between prophylactic antimicrobials
and recurrent UTI, and (3) determine
the risk factors for resistance among
recurrent UTIs.
METHODS
Design
We assembled a cohort of children aged
6 years or younger who were diag-
nosed with first UTI between July 1,
2001, and May 31, 2006. Time-to-
event analyses were used to determine
risk factors for recurrent UTI and ef-
fectiveness of antimicrobial prophy-
laxis. Time to event was defined as the
time from first UTI until recurrent UTI
(event of interest) or until last clinic
visit (observation censored without
event occurring). Among children with
recurrent UTI, a nested case-control
study was performed to identify risk fac-
180 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted)
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tors for resistant organisms as the cause
of the recurrent UTI. Power and
sample-size calculations indicated that
77 patients with recurrent UTI were
needed to have 90% power to detect a
hazard ratio of 1.5, assuming a 15% re-
currence rate, type I error of .05, and
1-year follow-up.
Setting
Patients were drawn from a network
of 27 primary care pediatric practices
spanning 3 states (Delaware, New Jer-
sey, and Pennsylvania) that share a
common electronic health record
(EHR) managed by The Children’s
Hospital of Philadelphia. The prac-
tices are located in urban, suburban,
and semirural locations. The institu-
tional review board of The Children’s
Hospital of Philadelphia approved the
study, waiving the need for patient
consent.
Data Sources
Data were extracted from the EHR used
by the 27 primary care pediatric prac-
tices in the research network. In addi-
tion to data entered at the point of care,
the EHR is automatically populated
with administrative and results data
from several other sources, including
the children’s hospital emergency de-
partment and main hospital as well as
2 laboratory vendors in the tri-state area
(Quest Diagnostics [Lyndhurst, New
Jersey] and LabCorp [Raritan, New
Jersey]).
Documents and results obtained
from hospitals and emergency depart-
ments outside the network also can be
scanned or manually entered into the
EHR by practice staff. The EHR con-
tains demographic and clinic visit in-
formation, laboratory data, radiology re-
sults, comorbid conditions coded using
the International Classification of Dis-
eases, Ninth Revision (ICD-9), and de-
tailed prescription data that were elec-
tronically extracted into the research
database. Antimicrobial sensitivity re-
sults for urinary pathogens and re-
sults for voiding cystourethrogram
(VCUG) could not be reliably ex-
tracted electronically; therefore, we re-
©2007 American Medical Association. All rights reserved.
viewed the patients’ EHR and manu-
ally entered urine antimicrobial
sensitivity and VCUG results into the
research database.
To minimize missing results from
outside the network, we also searched
the electronic and paper charts for cor-
respondence from outside hospitals and
clinics and included any results ob-
tained outside the network. All data ele-
ments were validated with the patient
chart as the gold standard on a 5% ran-
dom sample of patients, and all pre-
sumed patients with higher acuity (⬎2
hospitalizations). Abstracted data
agreed with the gold standard for all
data elements with greater than 95%
sensitivity and specificity.
Patients
The initial cohort (FIGURE) was de-
fined as all children aged 6 years or
younger with at least 2 clinic visits be-
tween July 1, 2001, and May 31, 2006
(N=74 974). Two clinic visits were re-
quired so that observation time could
be accrued. Microbiology records in the
EHR for these children were queried for
presence of positive urine culture re-
sults, defined as 50 000 colony-
forming units/mL or greater of a single
organism considered to be a urinary
tract pathogen, a criterion previously
validated for catheterized specimens;
775 children who had experienced a
first UTI were identified.18
The electronic and paper records (in-
cluding correspondence from outside
hospitals and clinics, problem lists, visit
notes, and microbiology results) of all
children with positive urine culture re-
sults were manually reviewed, and any
child with history of a previous UTI was
excluded (n = 91). To provide suffi-
cient observation time to develop a re-
current UTI (at least 14 days after a typi-
cal 10-day treatment course), children
with fewer than 24 days of observa-
tion time (n=55) were excluded. To as-
semble a cohort representative of oth-
erwise well children in the community,
we excluded 17 children with the fol-
lowing comorbid conditions defined a
priori based on ICD-9 codes from the
EHR: malignancy (140-239.xx), diabe-

tes (250.xx), human immunodefi-
ciency virus (042), other congenital im-
munodeficiencies (279.xx), sickle cell
disease (282.6), neurogenic bladder and
paralytic syndromes (343-344.xx), hy-
pertensive renal disease (403.xx), ne-
phritis and renal failure (580-589.xx),
renal calculi (592, 594), kidney disor-
ders (593.xx, except hydroureter and
VUR), chronic cystitis (595.xx, ex-
cept 595.0, acute cystitis), bladder and
urethra disorders (596, 598, and 599,
except 599.0 UTI), central nervous sys-
tem malformation (eg, myelomeningo-
cele; 655.0), and congenital anoma-
lies of the urinary system (753.xx). We
also excluded 1 child with a urine cul-
ture collected from a bag specimen.
Outcomes
Because children entered the cohort at
different times and had different lengths
of follow-up, time to recurrent UTI was
used as the primary outcome. The ob-
servation-time end point was defined
conservatively as the last clinic visit as
opposed to the end of study, because
we did not want to assume that chil-
dren were still within the primary care
network past their last documented
clinic visit. Recurrent UTI was de-
fined by a second positive urine cul-
ture result 2 or more weeks after the ter-
mination of therapy for the first UTI.
Of children with documented urine
collection methods, only 1 had urine
collected via bag specimen (ex-
cluded); all but 2 younger than 2 years
via catheterization; and all but 1 older
than 2 years via clean catch. Since col-
lection included specimens collected via
both catheterization and clean-catch, a
sensitivity analysis also was per-
formed in which results were recalcu-
lated using a cutoff of 100 000 colony-
forming units/mL or greater of a single
organism.
A survey of network nurse manag-
ers indicated that cultures were
obtained only if UTI symptoms were
present; to validate this claim, we per-
formed a 20% random sample chart re-
view of progress notes at UTI diagno-
sis to evaluate for presence of symptoms
documented consistent with UTI, in-
©2007 American Medical Association. All rights reserved.
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RECURRENT URINARY TRACT INFECTIONS IN CHILDREN
cluding fever, dysuria, and/or urinary
frequency. In the nested study of chil-
dren with recurrent UTI, the outcome
was resistance among recurrent UTIs.
Resistance was defined as a pathogen
resistant to any antimicrobial.
Exposures
Exposure variables were defined a priori
as age at first UTI, sex, race, VCUG re-
sult, prophylactic antimicrobial expo-
sure on a daily basis, and other antimi-
crobial exposure on a daily basis.
Antimicrobial prophylaxis prescrip-
tions were identified through a query
of electronic prescription records using
antimicrobial names, key terms such as
prophylaxis, and duration of prescrip-
tion. Each identified prescription,
blinded to the patient’s outcome, was
then manually reviewed to verify that
it represented UTI antimicrobial pro-
phylaxis. Any antimicrobial prescrip-
tion not considered UTI prophylaxis
was categorized as “other antimicro-
bial exposure.” VUR grade was based
on the maximum grade on either side
of the urinary collecting system. Re-
sults of VCUG were categorized a priori
as “not performed,” “normal,” “VUR
grade 1-3,” and “VUR grade 4-5.”19
Age was analyzed both ordinally by
year and dichotomized as age younger
than 2 years vs 2 to 6 years, based on
guidelines for imaging and prophy-
laxis specifically applying to children
younger than 2 years.10,12 Race and eth-
nicity were reported by parents in the
EHR. Less than 3% of the patients were
Hispanic, so ethnicity was not evalu-
ated separately. Race was considered as
white vs nonwhite, as there were less
than 3% Asian and no Native Ameri-
can patients.
Data Analysis
First, the incidence rates were calcu-
lated for first and recurrent UTI.
Single-variable time-to-event analysis
was performed for each exposure vari-
able to determine the hazard ratio
(HR) for the outcome of interest, time
to recurrent UTI. Sex, race, age at first
UTI, and VCUG result were consid-
ered fixed-time exposures. Prophylac-
(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 181
tic and other antimicrobial exposure
were considered time-varying vari-
ables, coded as “0” on days without
prescribed antimicrobials and “1” on
days that antimicrobials were pre-
scribed. This approach allowed accu-
rate modeling of the intermittent
nature of the antimicrobial exposure
and accounting for the effect of pro-
phylaxis on a daily basis for each
child. Multivariable Cox survival-time
regression was then performed to
identify risk factors for recurrent UTI.
A stratified analysis (defined a priori)
was performed for antimicrobial pro-
phylaxis hazard ratio by sex, age, race,
and VUR status to evaluate for effect
modification. To control for potential
confounding by indication that could
occur if physicians prescribed prophy-
laxis based on factors that increased the
risk of recurrence, a propensity score
also was developed for receipt of anti-
microbial prophylaxis, based on sex,
race, age at first UTI, and VCUG re-
sult.20 The propensity score model pre-
dicted receipt of prophylactic antimi-
crobials with good accuracy (c statistic,
0.81). We reanalyzed the effect of pro-
phylaxis in analyses stratified by quin-
tile of propensity score and in multi-
variable analyses controlling for
propensity score as a continuous and
categorical (quintiles) variable.
For comparison of resistant vs non-
resistant recurrent UTIs, univariable
logistic regression was performed to
measure the association between sex,
race, age at first UTI, VCUG result,
prophylactic antimicrobial exposure,
and other antimicrobial exposure to
the outcome of resistance. Since this
was not a time-to-event analysis, the
antimicrobial exposure variable was
defined as ever prescribed vs never
prescribed. The predicted probability
of the recurrent UTI being antimicro-
bial resistant for each combination of
exposures was calculated based on the
multivariable model (STATA predict
command). All analyses were per-
formed using STATA SE version 9.1
(StataCorp, College Station, Texas);
P ⬍ .05 was considered statistically
significant.
 RECURRENT URINARY TRACT INFECTIONS IN CHILDREN

RESULTS not have documented urine leukocyte

Table 1. First and Recurrent Urinary Tract
Infection (UTI) in The Children’s Hospital of Clinical Characteristics esterase and nitrite results. Of chil-
Pennsylvania Primary Care Cohort A total of 74 974 children aged 6 years dren with results, 473 (91%) of those
No. (%) or younger had at least 2 clinic visits with first UTI and 68 (95%) of those
between July 1, 2001, and May 31, with recurrent UTI had a positive uri-
First UTI Recurrent UTI
Characteristic (n = 611) (n = 83) 2006. Among these children, 666 had nalysis result, defined as presence of
Sex experienced a confirmed first UTI and leukocyte esterase or nitrites.18,21 In re-
Male a 68 (11.1) 8 (9.6) had no significant comorbid condi- view of progress notes for a 20% ran-
Female 543 (88.9) 75 (90.4) tions, resulting in a first-UTI inci- dom sample of first and recurrent UTI
Race
White 343 (56.1) 54 (65.1) dence rate in otherwise healthy chil- events, all children had symptoms con-
Nonwhite 268 (43.9) 29 (34.9) dren of 0.007 per person-year. Fifty- sistent with UTI including fever, dys-
Age, y five children had fewer than 24 days of uria, and/or urinary frequency at the
⬍2 236 (38.6) 26 (31.3) observation, leaving 611 children in the time of diagnosis. The mean observa-
2-6 375 (61.4) 57 (68.7) final analytic cohort. Eighty-three tion time for the cohort with first UTI
VCUG result (13.6%) of these children experienced was 408 days (median, 310 days; in-
Not performed 400 (65.5) 52 (62.7)
Normal 154 (25.2) 20 (24.1) a recurrent UTI, resulting in a recur- terquartile range, 150-584 days).
VUR grade 1-3 50 (8.2) 8 (9.6) rent UTI incidence rate of 0.12 per per- The majority of the 611 children with
VUR grade 4-5 7 (1.1) 3 (3.6) son-year (12% recurrence per year). first UTI were female (543 [88.9%]),
Any exposure to Fifty-one (61%) of these recurrent UTIs white (343 [56.1%]), and aged 2 to 6
antimicrobial were caused by a pathogen with anti- years (375 [61.4%]). Most did not have
prophylaxis
No 483 (79.1) 64 (77.1) microbial resistance. Pathogens in- a VCUG performed (400 [65.5%]) and
Yes 128 (20.9) 19 (22.9) cluded Escherichia coli (78%), other had not received antimicrobial prophy-
Abbreviations: VCUG, voiding cystourethrogram; VUR, vesi- gram-negative rods (16%), Enterococ- laxis (483 [79.1%]) (TABLE 1). Chil-
coureteral reflux.
a Among male children, there was no documented circum- cus (4%), and other organisms (2%). dren younger than 2 years were more
cision status for 32 (47%); of those with documented sta-
tus, 26 (38%) were uncircumcised, and 10 (15%) were
Fifteen percent of children in both the likely to have a VCUG performed (137
circumcised. first and the recurrent UTI groups did [58%]) compared with children older
than 2 years (75 [20%]). Prophylactic
antimicrobials prescribed included cot-
Table 2. Time-to-Event Analysis for Risk of Recurrent Urinary Tract Infection (UTI) a rimoxazole (61%), amoxicillin (29%),
HR (95% CI) nitrofurantoin (7%), and other antimi-
Characteristic Univariable Multivariable b crobials including first- through third-
Sex generation cephalosporins (3%). Of the
Male 1 [Reference] 1 [Reference] 68 male children, there was no docu-
Female 1.20 (0.58-2.50) 1.08 (0.51-2.30) mented circumcision status for 32
Race (47%). Twenty-six (38%) were uncir-
Nonwhite 1 [Reference] 1 [Reference]
White 1.99 (1.26-3.16) c 1.97 (1.22-3.16) c
cumcised and 10 (15%) were circum-
Age, y cised.
⬍1 1 [Reference] 1 [Reference]
1 to ⬍2 0.99 (0.43-2.27) 1.05 (0.20-3.37) Risk of Recurrent UTI
2 to ⬍3 1.22 (0.51-2.95) 1.26 (0.51-3.07) and Association With
3 to ⬍4 2.55 (1.33-4.81) c 2.75 (1.37-5.51) c Antimicrobial Prophylaxis
4 to ⬍5 2.17 (1.10-4.29) c 2.47 (1.19-5.12) c In both univariable and multivariable
5 to ⱕ6 1.36 (0.66-2.80) 1.62 (0.73-3.62)
Cox survival time regression (TABLE 2),
VCUG
Normal result 1 [Reference] 1 [Reference] the risk of recurrent UTI was in-
Not performed 1.00 (0.60-1.68) 0.70 (0.40-1.21) creased by white race (0.17 per person-
VUR grade 1-3 1.17 (0.52-2.66) 1.05 (0.43-2.57) year; multivariable HR, 1.97; 95% con-
VUR grade 4-5 4.59 (1.36-15.47) d 4.38 (1.26-15.29) d fidence interval [CI], 1.22-3.16), age 3
Antimicrobial prophylaxis e 1.05 (0.57-1.94) 1.01 (0.50-2.02) f to 4 years (0.22 per person-year; mul-
Abbreviations: CI, confidence interval; HR, hazard ratio; VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux.
a Time-to-event analysis performed from date of first UTI until event, recurrent UTI, or last clinic visit within the network.
tivariable HR, 2.75; 95% CI, 1.37-
b Multivariable time-to-event analysis controlling for sex, race, age, VCUG result, and time-varying exposure to antimi- 5.51), age 4 to 5 years (0.19 per person-
crobial prophylaxis. year; multivariable HR, 2.47; 95% CI,
c P ⬍ .01.
d P ⬍ .05.
e Exposure to antimicrobial prophylaxis was modeled as a time-varying covariate on a daily basis to take into account
1.19-5.12), and grade 4 to 5 VUR (0.60
the intermittent nature of exposure and provide the most powerful estimate of its effect over time. per person-year; multivariable HR, 4.38;
f Adjusting antimicrobial prophylaxis by propensity score quintile, continuous propensity score, and propensity score in
addition to all covariates produced HRs of 1.03, 1.02, and 1.01, respectively.
95% CI, 1.26-15.29). When age was
considered as a dichotomous variable,
182 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted) ©2007 American Medical Association. All rights reserved.

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 RECURRENT URINARY TRACT INFECTIONS IN CHILDREN

2- to 6-year olds had significantly in-

Table 3. Risk of Antimicrobial Resistance Among Children With Recurrent Urinary Tract
creased risk of recurrent UTI (HR, 2.01; Infection (UTI)
95% CI, 1.20-3.37). Sex, grade 1 to 3 Resistant UTIs, Antimicrobial-Resistant
VUR, and other antimicrobial expo- Characteristic No. (%) Recurrent UTI, OR (95% CI) a
sure had no effect on risk of recurrent Total 51 (61.4)
UTI. Among male children in whom Sex
Male 7 (87.5) 1 [Reference]
circumcision status was known, 5 of 26
Female 44 (58.7) 0.20 (0.02-1.73)
(19%) uncircumcised vs 0 of 10 cir-
Race
cumcised children had a recurrent UTI Nonwhite 24 (82.8) 1 [Reference]
(P=.13). White 27 (50.0) 0.21 (0.07-0.63) b
Antimicrobial prophylaxis expo- Age, y
sure considered as a time-varying co- ⬍2 21 (80.8) 1 [Reference]
variate had no significant effect on the 2-6 30 (52.6) 0.26 (0.09-0.80) c
risk of recurrent UTI in multivariable VCUG
Normal result 14 (70.0) 1 [Reference]
analysis (HR, 1.01; 95% CI, 0.50-
Not performed 27 (51.9) 0.46 (0.15-1.39)
2.02). In stratified analyses for each of
VUR grade 1-3 7 (87.5) 3.00 (0.30-30.02)
the other covariates (sex, race, age, and
VUR grade 4-5 3 (100) NA d
VCUG result), antimicrobial prophy-
VUR grades 1-5 4.29 (0.44-41.37)
laxis had no significant effect in any of
Antimicrobial prophylaxis
the groups. Analyses stratified by pro- Not exposed 34 (53.1) 1 [Reference]
pensity score quintile also demon- Exposed 17 (89.5) 7.50 (1.60-35.17) b
strated no significant effect of antimi- Abbreviations: CI, confidence interval; NA, not available; OR, odds ratio; VCUG, voiding cystourethrogram; VUR, vesi-
crobial prophylaxis. Similarly, coureteral reflux.
a OR of resistant vs pan-sensitive organism as the cause of recurrent UTI.
antimicrobial prophylaxis did not de- b P ⬍ .01.
c P ⬍ .05.
crease the risk of recurrent UTI when d All (3/3) children with recurrent UTI and with grade 4-5 VUR had resistant infections, so OR is infinite and no CI was
controlling for the propensity quintile calculated.

(HR, 1.03; 95% CI, 0.51-2.08), propen-

sity score as a continuous variable (HR,
1.02; 95% CI, 0.51-2.05), or propen-
sity score combined with all covari-
ates (HR, 1.01; 95% CI, 0.51-2.02).
Analysis stratified by type of antimi-
crobial prophylaxis demonstrated no as-
sociation between type of prophylaxis
and risk of recurrent UTI; however, a
HR for nitrofurantoin prophylaxis could
not be calculated because 0 of 9 chil-
dren receiving nitrofurantoin experi-
enced a recurrent UTI.
Risk of Resistance Among Children
With Recurrent UTI
Among the 83 children with recurrent
UTI, white race (odds ratio [OR], 0.21;
95% CI, 0.07-0.63) and age 2 to 6 years
(OR, 0.26; 95% CI, 0.09-0.80) were as-
sociated with decreased risk of resis-
tant infections. Conversely, exposure
to prophylactic antimicrobials signifi-
cantly increased the likelihood of re-
sistant infections (OR, 7.50; 95% CI,
1.60-35.17) (TABLE 3). This increased
risk of resistance associated with anti-
microbial prophylaxis persisted when
controlling for the antimicrobial re-
©2007 American Medical Association. All rights reserved.
ceipt propensity score (OR, 6.76; 95%
CI, 1.26-30.57) and whether the first
UTI was resistant (OR, 8.66; 95% CI,
1.66-45.31). Any exposure to other
(nonprophylactic) antimicrobials and
exposure to other antimicrobials in the
30 days prior to a recurrent UTI were
not significantly associated with resis-
tant infections. Age at first UTI, VCUG
result, and exposure to antimicrobial
prophylaxis were highly correlated
(P ⬍ .001 for all) among the 83 chil-
dren with recurrent UTI, likely due to
the American Academy of Pediatrics
guideline recommending that a VCUG
be performed in children younger than
2 years and prophylaxis given to those
children with VUR.10 Since this colin-
earity prevents the ascertainment of the
effect of each individual exposure in a
multivariable model and we wanted to
provide clinicians with a risk profile
based on exposures, we calculated the
predicted probability of a recurrent UTI
being antimicrobial resistant (TABLE 4)
for each combination of exposures de-
rived from a multivariable regression
model that included race, age, pres-
(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 183
ence of VUR, and exposure to antimi-
crobial prophylaxis. For example, a
nonwhite child younger than 2 years
who has VUR and is exposed to anti-
microbial prophylaxis has the highest
probability of resistance, 98.0%
(Table 4). In contrast, a white 2- to
6-year-old child who does not have
VUR and is not exposed to prophy-
laxis has only a 40.4% probability of a
resistant recurrent UTI. If this same
white, 2- to 6-year-old child without
VUR is exposed to prophylaxis, our data
predict an increased absolute probabil-
ity of resistance of more than 30% to
73.3%, demonstrating that exposure to
antimicrobial prophylaxis has a major
impact on risk of resistance in recur-
rent UTIs.
COMMENT
To our knowledge, this study is the first
large primary care pediatric cohort
study to evaluate risk factors for recur-
rent UTI and the association with an-
timicrobial prophylaxis. We found that
antimicrobial prophylaxis was not as-
sociated with lower risk of recurrent

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 RECURRENT URINARY TRACT INFECTIONS IN CHILDREN

However, in analyses stratified by VUR

Table 4. Probability of Recurrent Urinary Tract Infection Being Antimicrobial Resistant Based
on Exposures grade, our study found that antimicro-
Exposure Type bial prophylaxis had no significant
effect on risk of recurrence for chil-
Nonwhite VUR Prophylactic Antimicrobial Probability of dren with either grade 1 to 3 or grade
Race Age ⬍2 y Present Exposure Resistance, % a
⫹ ⫹ ⫹ ⫹ 98.0
4 to 5 VUR, but no firm conclusions
⫹ − ⫹ ⫹ 97.2
could be made in the grade 4 to 5 VUR
⫹ ⫹ − ⫹ 94.2
group, which had only 7 children. Pre-
⫹ ⫹ ⫹ − 92.4 vious randomized trials also have dem-
− ⫹ ⫹ ⫹ 92.2 onstrated the lack of effectiveness of
⫹ − − ⫹ 92.0 prophylaxis to prevent recurrent UTI
⫹ − ⫹ − 89.6 and renal scarring in children with
− − ⫹ ⫹ 89.3 grade 1 to 3 VUR.5,16 Therefore, it is un-
⫹ ⫹ − − 79.9 clear how much of a role the presence
− ⫹ − ⫹ 79.5 of VUR, especially low-grade VUR,
− ⫹ ⫹ − 74.5 should play in making decisions about
⫹ − − − 73.8 starting prophylactic antimicrobials.
− − − ⫹ 73.3 Our study demonstrated that age may
− − ⫹ − 67.4 be an important consideration for risk
− ⫹ − − 48.9 of recurrent UTI and antimicrobial-
− − − − 40.4 resistant infections. Children aged 2 to
a Probability of causative organism for recurrent urinary tract infection being resistant to any antimicrobial based on 6 years, especially those aged 3 to 5
multivariable model including race, age, presence of vesicoureteral reflux (VUR), and antimicrobial prophylaxis
exposure. years, were at increased risk of recur-
rent UTI, possibly related to dysfunc-
tional elimination that previously has
UTI but was associated with increased timicrobial prophylaxis was associ- been identified as an underappreci-
risk of resistant infection. ated with significantly increased risk of ated risk factor.24-29 The observed in-
Also, to our knowledge, this is the resistant infections. The results did not creased risk of recurrent UTI in older
first study to estimate the incidence of change significantly when a more strin- children is contrary to previous con-
recurrent UTI after an initial UTI in a gent colony-count criterion (ⱖ100 000 cerns that younger children are at high-
large primary care pediatric cohort. The colony-forming units/mL) was used to est risk. Those concerns were based
incidence of first UTI, 0.007 per person- define a positive urine culture result. largely on the findings from a study of
year (4.2% cumulative incidence from Recent randomized trials of antimicro- Swedish children recruited from
ages 0-6 years), is similar to previous bial prophylaxis also have demon- Goteborg hospital in the 1960s.1,8 How-
population-based first-UTI cumula- strated no reduction in risk of UTI re- ever, that study included catheteriza-
tive incidence rate estimates of 2% to currence or renal scarring.5,16 Given tions performed at set follow-up times
8%.1,22 The rate of recurrent UTI (0.12 these previous findings and the unfa- irrespective of the presence of symp-
per person-year, or 12% per year) was vorable risk/benefit ratio demon- toms, which may have biased it to-
lower than recurrence rates previ- strated by the current study, we think ward detecting persistent asymptom-
ously reported from referral popula- it is prudent for clinicians to discuss the atic bacteriuria in younger infants,
tions or populations with cultures per- risks and unclear benefits of prophy- rather than recurrent UTI. Thus our
formed without symptoms (20%-48% laxis with families as they make family- study, which defined recurrent UTI
within 6-12 months).1,4-9 The estimate centered decisions about whether to based on physician diagnosis trig-
of recurrent UTI incidence was the same start prophylactic antimicrobials or to gered by symptoms, may better reflect
as that in a study that reported a 12% closely monitor a child without pre- the epidemiology of recurrent symp-
recurrence rate after diagnosis of first scribing antimicrobial prophylaxis af- tomatic UTI in a pediatric primary
UTI in an emergency department23 and ter a first UTI. care population. 1,8 Interestingly, a
probably better represents the inci- Currently, antimicrobial prophy- 2006 population-based study from the
dence of symptomatic recurrent UTI in laxis is recommended if a child has Netherlands found results similar to
a primary care setting. VUR.10,12 In analyses controlling for an- ours—in that study, the maximal inci-
No association was found between timicrobial exposure, our study found dence of UTI in both girls and boys was
antimicrobial prophylaxis and risk of no significantly increased risk of recur- in year 4 of life.30
recurrent UTI, either in multivariable rence for children with grade 1 to 3 Race also may play a role in risk of
Cox regression or in propensity score VUR and increased risk of recurrence recurrent UTIs and resistant infec-
analyses. In addition, exposure to an- in children with grade 4 to 5 VUR. tions. Nonwhites had a decreased risk
184 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted) ©2007 American Medical Association. All rights reserved.

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of recurrent UTI yet an increased risk
of resistant infections. All 9 recurrent
UTIs in nonwhites exposed to prophy-
lactic antimicrobials were caused by a
resistant organism. We are not aware
of literature to explain the mechanism
for increased risk of resistance, but it
raises questions about whether the ben-
efits of antimicrobial prophylaxis ex-
ceed the risks in nonwhite children.
Clearly, more studies are needed to vali-
date these findings and to explore the
genetic and environmental basis for this
observation.
Our study has several limitations.
First, as with all studies in which data
are gathered via health care delivery net-
works, we could have missed results
from outside the network. We at-
tempted to minimize this loss through
incorporation of results from outside
hospitals and clinics. Second, if pat-
terns of care were different between
groups, then ascertainment bias could
have occurred. For example, if whites
were more likely than nonwhites to seek
or receive care or testing for urinary
symptoms, then that pattern of care
could explain the observed increased
risk of recurrent UTI in whites. How-
ever, we found no evidence to support
this explanation—there was no signifi-
cant difference between races in the
number of clinic visits per year overall
or after first UTI diagnosis.
Third, 65% of the children in our
study did not have VCUGs per-
formed; the majority of these children
were older than 2 years, for whom the
American Academy of Pediatrics guide-
line is silent regarding recommenda-
tions on screening for VCUG.10 But this
prevented us from fully exploring the
effect of VUR on recurrent UTI and the
effectiveness of prophylactic antimi-
crobials by VUR grade. Fourth, the lack
of circumcision documentation in 47%
of male children limited our ability to
accurately assess risk based on this im-
portant factor. Fifth, we based expo-
sure to antimicrobial prophylaxis on an-
timicrobial prescriptions and therefore
likely overestimated the degree of an-
timicrobial exposure in children both
with and without recurrent UTI, be-
©2007 American Medical Association. All rights reserved.
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RECURRENT URINARY TRACT INFECTIONS IN CHILDREN
cause they may not have adhered to
their prescribed regimen. This could
have biased the effect of prophylactic
antimicrobials toward the null. Sixth,
our measure of the effectiveness of an-
timicrobial prophylaxis could have been
affected by confounding by indica-
tion. We attempted to minimize this
confounding by controlling for plau-
sible observed factors that could influ-
ence the decision of a clinician to pre-
scribe prophylaxis, such as sex, race,
age, and VUR status, and by perform-
ing multiple propensity score analy-
ses.20,31 However, we must recognize
that residual unobservable confound-
ing could exist in the assessment of pro-
phylaxis efficacy. Finally, because less
than 5% of children underwent dimer-
captosuccinic acid renal scintigraphy to
assess for pyelonephritis and renal scar-
ring, we could not comment on the
effect of prophylaxis on these out-
comes.
The major strength of this study is
that it is the first study of a large pedi-
atric primary care cohort to simulta-
neously examine the risks and ben-
efits of antimicrobial prophylaxis for
children with first UTI. This study as-
sessed more than 600 children after first
UTI in a “natural experiment” setting
for, on average, more than 1 year, which
is an adequate duration to assess the ef-
fectiveness of antimicrobial prophy-
laxis in practice. Conducting the study
in a primary care setting also freed it
of the selection bias that has limited the
generalizability of previous studies,
which typically were performed in re-
ferral populations.
Given the limitations of observa-
tional studies, further investigation is
needed to better understand the risks
and benefits of antimicrobial prophy-
laxis. Specifically, a randomized trial in-
volving children in the community set-
ting after first UTI comparing daily
prophylaxis vs close follow-up would
significantly improve understanding of
the efficacy of antimicrobial prophy-
laxis. Based on our findings, this type
of study should be powered to exam-
ine the efficacy of prophylaxis in pa-
tient subgroups including nonwhites,
(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 185
older children, and those with and with-
out VUR. It also will be important for
future studies to evaluate the poten-
tial risks of prophylaxis, such as resis-
tant infections.
CONCLUSIONS
White race, age 3 to 5 years, and grade
4 to 5 VUR were associated with in-
creased risk of recurrent UTI. Sex and
grade 1 to 3 VUR were not associated
with risk of recurrence. Antimicrobial
prophylaxis was not associated with
lower risk of recurrent UTI, but pro-
phylaxis was associated with in-
creased risk of resistant infections.
Author Contributions: Dr Conway had full access to all
of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Conway, Cnaan, Zaoutis,
Grundmeier, Keren.
Acquisition of data: Conway, Cnaan, Henry,
Grundmeier, Keren.
Analysis and interpretation of data: Conway, Cnaan,
Zaoutis, Keren.
Drafting of the manuscript: Conway, Cnaan, Keren.
Critical revision of the manuscript for important in-
tellectual content: Conway, Cnaan, Zaoutis, Henry,
Grundmeier, Keren.
Statistical analysis: Conway, Cnaan, Henry, Keren.
Obtained funding: Conway, Zaoutis, Keren.
Administrative, technical, or material support: Henry,
Grundmeier, Keren.
Study supervision: Cnaan, Keren.
Financial Disclosures: None reported.
Funding/Support: Dr Conway was supported by a
training grant through the Robert Wood Johnson Clini-
cal Scholars Training Program. This project was sup-
ported through a pilot grant from a University of Penn-
sylvania Center for Education and Research on
Therapeutics (CERTS) grant. Dr Cnaan is supported
by National Institutes of Health (NIH) Clinical and
Translational Science Award U54 RR023567-01. Dr
Keren was supported by grant K23 HD043179 from
the National Institute of Child Health and Human De-
velopment, NIH.
Role of the Sponsors: None of the funding sources
had any role in the design and conduct of the study;
the collection, management, analysis, and interpre-
tation of the data; or the preparation, review, or ap-
proval of the manuscript.
Additional Contributions: We thank the physicians
and staff of the Practice-Based Research Network,
especially Marguerite Swietlik, CRNP, and Louis Bell,
MD, who facilitated the performance of this study.
We thank Chris Bell for research support and data
collection and Huaqing Zhao, MSc, The Children’s
Hospital of Pennsylvania Biostatistics and Data Man-
agement Core, for statistical support. None of those
ackowledged received any compensation for their
contributions.
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