Recurrent Urinary Tract Infections:
Risk Factors and Effectiveness of
Prophylaxis in a Primary Care Cohort
AcademyHealth Annual Meeting
Patrick H. Conway, MD, MSc
Avital Cnaan, PhD
Theoklis Zaoutis, MD, MSCE
Brandon Henry, BS
Robert Grundmeier, MD
Ron Keren, MD, MPH
Epidemiology
 Urinary tract infection (UTI) is the most
common serious bacterial infection in
children
 Estimates of cumulative incidence in
children 0 - 6 years suggest 70,000 to 180,000
of the annual U.S. birth cohort will have a UTI
by age six
 Little data on recurrent UTI rate but previous
estimates of 20 - 48% within 6-12 months
Traditional Conceptual Model
Figure 1 Conceptual Model
Prophylactic
antibiotics prevent
recurrent UTI
End Stage Renal
Disease
UTI(s)
RENAL
SCARRING
Hypertension
Surgery
corrects VUR
Pre-eclampsia
VUR
Controversy
 Cochrane report summarized that
evidence “to support widespread use
of antibiotics to prevent recurrent UTI
is weak”
 Two small clinical trials found
prophylaxis had no significant effect on
risk of recurrent UTI or renal scarring
Specific Aims
1. To determine the factors associated with
risk of recurrent UTI in a primary-care
based cohort and to estimate the risk
reduction provided by prophylactic
antibiotics
2. To determine the risk factors for antibiotic
resistance among recurrent UTIs
Methods: Data Source
 Data obtained from primary care based
network of practices who contribute to
CHOP’s Epic electronic health record
 27 practices from urban, suburban, and
semi-rural areas in 3 states
 Data contains laboratory, prescription,
and radiology data from clinic and
emergency room settings
Cohort Inclusion Criteria
 Identified children 0 - 6 years of age with at
least 2 office visits between 7/1/2001 and
5/31/2006
 From these infants, identified cohort with
first UTI based on positive urine culture
(>50,000 CFU/ml single organism)
 Followed infants until last documented
contact with the network or until they
experienced the primary outcome, a
recurrent UTI
Aim 1
 Design: Cohort
 Outcome variable: Time to recurrent UTI
 Covariates:
 Age at first UTI
 Gender
 Race
 Degree of reflux
 Antibiotic prophylaxis
 Antibiotic prophylaxis was considered as a
time varying covariate
 Analysis: Cox survival time regression
Aim 2
 Design: Nested case-control
 Outcome variable: Resistant versus pansensitive recurrent infections
 Covariates:
 Age at first UTI
 Gender
 Race
 Antibiotic prophylaxis exposure (yes/no)
 Degree of reflux
 Analysis: Multivariable logistic regression
Results
74,974 Children 0-6
years of age with at
least 2 clinic visits
719 Children with any
Urinary Tract Infection
628 Children with First UTI
611 Children with First
UTI and not Excluded
83 Children with
Recurrent UTI
First UTI
incidence rate:
0.007 per
person-year
Recurrent UTI
incidence rate:
0.12 per personyear
Observation time
 Mean observation time was 408 days
with a median of 310 days (IQR 150 –
584 days), range of 24 - 1600 days
First and Recurrent UTI
First UTI (Number, %)
Total
Recurrent UTI (Number, %)
611
83 (13.6)
Gender
- Male
- Female
68 (11.1)
543 (88.9)
8 (9.6)
75 (90.4)
Race
- Caucasian
- Non-Caucasian
343 (56.1)
268 (43.9)
54 (65.1)
29 (34.9)
236 (38.6)
375 (61.4)
26 (31.3)
57 (68.7)
VCUG
- Not Performed
- Normal
- VUR Grade 1 - 3
- VUR Grade 4 - 5
400 (65.5)
154 (25.2)
50 (8.2)
7 (1.1)
52 (62.7)
20 (24.1)
8 (9.6)
3 (3.6)
Exposure to antibiotic
prophylaxis
- No
- Yes
483 (79.1)
128 (20.9)
64 (77.1)
19 (22.9)
Age
- Less than 2 years
- 2 - 6 years
Risk of Recurrent UTI1
Univariable Hazard
Ratio (95% CI)
Multivariable Hazard
Ratio2 (95% CI)
Gender (Ref. Male)
- Female
1.20 (0.58 – 2.50)
1.08 (0.51 – 2.30)
Race (Ref. Non-Caucasian)
- Caucasian
1.99 (1.26 – 3.16)3
1.97 (1.22 – 3.16)3
Age (Ref. 0 - 1 year)
-1 – 2 years
-2 – 3 years
-3 – 4 years
-4 – 5 years
-5 – 6 years
0.99 (0.43 – 2.27)
1.22 (0.51 – 2.95)
2.55 (1.33 – 4.81)3
2.17 (1.10 – 4.29)3
1.36 (0.66 – 2.80)
1.05 (1.20 – 3.37)
1.26 (0.51 – 3.07)
2.75 (1.37 – 5.51)3
2.47 (1.19 – 5.12)3
1.62 (0.73 – 3.62)
VCUG (Ref. Normal)
-Not Performed
-VUR Grade 1-3
-VUR Grade 4-5
1.00 (0.60 – 1.68)
1.17 (0.52 – 2.66)
4.59 (1.36 – 15.47)4
0.70 (0.40 – 1.21)
1.05 (0.43 – 2.57)
4.38 (1.26 – 15.29)4
Antibiotic prophylaxis5
1.05 (0.57 – 1.94)
1.016 (0.50 – 2.02)
1
Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care network
Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure
3 p<0.01
4 p<0.05
5 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed and
intermittent nature of exposure
2
100
75
50
25
0
Percent without Recurrence
Time To Recurrent UTI by Age
0
12
24
36
Observation Time (months)
Age < 2 Years
Age ≥ 2 – 6 Years
Antibiotic Prophylaxis
Propensity Score Analysis
 Developed a propensity score for likelihood of
receipt of prophylactic antibiotics
 Analyses stratified by propensity score
quintile demonstrated no significant effect of
antibiotic prophylaxis
 Antibiotic prophylaxis still did not decrease
risk of recurrent UTI when controlling for:
• Propensity quintile (HR 1.03, 0.51 – 2.08 )
• Continuous propensity score (HR 1.02, 0.51 – 2.05 )
Risk of Antibiotic Resistance among Recurrent UTI Subjects
Number of Resistant
Infections (% of
Recurrent UTI subjects)
Odds Ratio of
Recurrent UTI Being
Antibiotic Resistant1
95% CI
Gender
- Male
- Female
7 (87.5)
44 (58.7)
Ref
0.20
0.02 – 1.73
Race
- Non-Caucasian
- Caucasian
24 (82.8)
27 (50.0)
Ref
0.212
0.07 – 0.63
21 (80.8)
30 (52.6)
Ref
0.263
0.09 – 0.80
VCUG
- Normal
- Not Performed
- VUR Grade 1-3
- VUR Grade 4-5
14 (70.0)
27 (51.9)
7 (87.5)
3 (100.0)
Ref
0.46
3.00
NA
0.15 – 1.39
0.30 – 30.02
NA
Antibiotic prophylaxis
- None
- Exposed to prophylaxis
34 (53.1)
17 (89.5)
Ref
7.502
1.60 – 35.17
Age
- Less than 2 years
- 2 – 6 years
1
Odds ratio of resistant versus pan-sensitive organism as cause of recurrent UTI
p ≤ 0.01
3 p < 0.05
2
Probability of Recurrent UTI Being Antibiotic Resistant1
Prophylactic
Antibiotic exposure
1
2
NonCaucasian
Less than 2
Years of Age
VUR
Present
Probability of
Resistance (%)2
+
+
+
+
98.0
+
+
+
-
94.2
-
+
+
+
92.4
+
-
+
+
92.2
-
+
-
+
89.6
+
-
-
+
89.3
-
+
+
-
79.9
+
-
+
-
79.5
-
-
+
+
74.5
-
+
-
-
73.8
+
-
-
-
73.3
-
-
+
-
48.9
-
-
-
-
40.4
For each exposure variable, a “+” represents that exposure being present
Probability of causative organism being resistant to any antibiotic
Summary
 Incidence rate for recurrent UTI of 12% per
year is significantly lower than previous
estimates
 Prophylactic antibiotics not associated with
decreased risk of recurrent UTI but
significantly associated with increased the
risk of resistant infections
 Older 2-6 year old children, especially age 35, and Caucasian children had an increased
risk of recurrent UTI
 VUR Grade 1-3 had no significant effect on
recurrence risk
Limitations – Antibiotic exposure
 Antibiotic exposure was based on
prescription data
 Likely overestimates the exposure in
both subjects with and without
recurrent UTI
 Potential confounding by indication
and residual unobservable
confounding
Limitations – Sparse or Missing Data
 Missing data due to VCUG not being
performed
 Possibility of missing data from
outside network
• Attempted to minimize through chart
review including correspondence
from outside hospitals and clinics
Strengths
 Based on primary care population
 Cohort design with large sample size that
followed subjects for on average over 1 year
in “natural experiment”
 Concurrently investigates potential risks
and benefits of prophylactic antibiotics in
same cohort
Implications – Antibiotic Prophylaxis
 Given potential lack of prevention benefit
and demonstrated harm due to resistant
infections, this study in combination with
other negative RCTs raises doubts about the
effectiveness of prophylactic antibiotics
 Close monitoring without prophylaxis after
first UTI may be a reasonable management
strategy
Implications - VUR and Antibiotic Prophylaxis
 Subjects with Grade 1-3 VUR had no
significant increased risk of recurrence and
Grade 4-5 VUR had increased recurrence risk
 Antibiotic prophylaxis did not effect the risk
of recurrence in either group in stratified or
multivariable analysis
 Unclear if VUR, especially lower grade VUR,
should be sole factor considered in
prophylaxis recommendations
Implications – Other Risk Factors
 Non-Caucasians had decreased risk of
recurrence but increased risk of
resistant infections
 Older children (age 2-6 years) had
increased risk of recurrence; this may
represent dysfunctional elimination
syndromes
Next Steps and Considerations
 RCT of antibiotic prophylaxis versus close
monitoring
 Should UTI be considered as 2 hits
necessary prior to long-term treatment?
• Child with first UTI and no major urinary tract
anomalies watched closely off treatment
 Future studies should validate whether older
age and Caucasian race are risk factors for
recurrence and explore mechanisms (e.g.
dysfunctional elimination, genetic markers)
Acknowledgments




University of Pennsylvania CERTS grant
Dr. Ron Keren
Dr. Avital Cnaan
Mr. Brandon Henry and Chris Bell, research
assistants
 University of Pennsylvania Clinical Scholars
Program
 Practice-Based Research Network at CHOP,
its physicians, staff, and patients
Males by Circumcision Status
First UTI (Number) Recurrent UTI
(Number, %)1
Uncircumcised
26
5 (19.2)
Circumcised
10
0 (0)
Unknown
32
3 (9.4)
Total
68
8 (11.8)
1 Differences
were not statistically significant
Effect of Antibiotic Prophylaxis Stratified
by VUR Status1
Hazard Ratio for Antibiotic
Prophylaxis2 (95% CI)
VCUG
- Normal
- Not Performed
- VUR Present
1
0.27 (0.04 – 2.02)
1.44 (0.57 – 3.64)
0.95 (0.29 – 3.13)
Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care
network
2 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed
and intermittent nature of exposure
Risk of Recurrent UTI in Females1
Multivariable Hazard
Ratio2 (95% CI)
1
Race (Ref. Non-Caucasian)
- Caucasian
2.12 (1.27 – 3.54)3
Age (Ref. Less than 2 years)
- 2 - 6 years
1.94 (1.11 – 3.38)4
VCUG (Ref. Normal)
- Not Performed
- VUR Grades 1 - 3
- VUR Grades 4 - 5
0.69 (0.39 – 1.22)
1.03 (0.39 – 2.66)
2.51 (.33 – 19.3)
Antibiotic prophylaxis5
1.04 (0.49 – 2.18)
Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care
network
2 Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure
3 p<0.01
4 p<0.05
5 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed
and intermittent nature of exposure
Risk of Recurrent UTI in Males1
Multivariable Hazard
Ratio2 (95% CI)
1
Race (Ref. Non-Caucasian)
- Caucasian
0.59 (.10 – 3.74)
Age (Ref. Less than 2 years)
- 2 - 6 years
2.30 (.48 – 11.1)
VCUG (Ref. Normal)
- Not Performed
- VUR Grades 1 - 3
- VUR Grades 4 - 5
1.24 (0.19 – 8.21)
1.36 (0.48 – 11.1)
16.1 (1.91 – 136)
Antibiotic prophylaxis5
1.73 (0.18 – 16.52)
Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care
network
2 Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure
3 p<0.01
4 p<0.05
5 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed
and intermittent nature of exposure
Risk of Recurrent UTI by 1 Year Age Groups1
Multivariable Hazard
Ratio2 (95% CI)
Gender (Ref. Male)
- Female
Race (Ref. Non-Caucasian)
- Caucasian
1.97 (1.22 – 3.16)3
Age (Ref. 0 – 1 year)
- 1 – 2 years
- 2 – 3 years
- 3 – 4 years
- 4 – 5 years
- 5 – 6 years
1.05 (.45 – 2.47)
1.26 (.51 – 3.07)
2.75 (1.37 – 5.51)3
2.46 (1.19 – 5.11)4
1.62 (.73 – 3.62)
VCUG (Ref. Normal)
- Not Performed
- VUR Grades 1 - 3
- VUR Grades 4 - 5
0.68 (0.39 – 1.21)
1.14 (0.47 – 2.82)
4.38 (1.25 – 15.29)4
Antibiotic prophylaxis5
1
1.08 (0.51 – 1.96)
0.97 (0.48 – 1.96)
Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care network
Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure
3 p<0.01
4 p<0.05
2
Other Recurrent UTI Studies
 Winberg studies published in ‘73 and ‘74 based
on children 0-16 years who presented to
Children’s Hospital in Goteborg from 1960-66
 Proposed it was population based as “few other
clinics” in the area
 After first UTI, children had urine tested at 13, 30,
60, and 90 days after first UTI and then at 1, 3, and
5 years after first UTI (not necessarily based on
symptoms)
 Recurrence rate of 29% overall
 Decreasing “recurrence” rate with boys over time
but no comment on circumcision status of males
Other Recurrent UTI Studies
(cont)
 Panaretto et al (J Paed Child Health 99)
• 290 children 0-5 years diagnosed with UTI
in ED, then had follow-up with 261 that
consisted of phone call to parents at 6 and
12 months after UTI
• If parents reported UTI recurrence, then
investigators attempted to confirm via
culture
• Found 13% recurrence rate
Other Recurrent UTI Studies
(cont)
 Garin et al 2006 demonstrated no significant
different recurrence risk in prophylaxis
group versus no prophylaxis group (17 vs
23% overall)
 9% pyelonephritis in prophylaxis group
versus 3% in no prophylaxis group
 Among children on prophylaxis, recurrence
rate of 8.8% for subjects without VUR versus
23.6% for those with VUR
Cochrane Review
• Trials by Savage, Smellie, Stansfield in
70’s of prophylaxis versus placebo
• Often included children with multiple
previous UTIs, no blinding, and testing of
urine without symptoms
• Recurrence rate as high as 69% in control
arm (savage)