1. Theoklis Zaoutis, MD, MSCE
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

2. Epidemiology
Urinary tract infection (UTI) is the most common serious bacterial infection in children
Estimates of cumulative incidence in children 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 % within 6-12 months

3. Traditional Conceptual Model
UTI ( s )
VUR
RENAL
SCARRING
End Stage Renal
Disease
Pre -
eclampsia
Hypertension
Prophylactic
antibiotics prevent
recurrent UTI
Surgery
corrects VUR
Figure 1
Conceptual Model
Model is Uti and vur leads to renal scarring which leads to ESRD and hypertension. Unfortunately, there is limited data about these links and the effects of prophylaxis and surgery in terms of preventing renal scarring

4. 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

5. Specific Aims
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

6. 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

7. Cohort Inclusion Criteria
Identified children 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
2 office visits so have observation time. 50,000 based on Hoberman paper ’94. Just say excluded kids with sig comorbidities

8. 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
Proph time varying on a daily basis

9. Aim 2 Design: Nested case-control
Outcome variable: Resistant versus pan-sensitive recurrent infections
Covariates:
Age at first UTI
Gender
Race
Antibiotic prophylaxis exposure (yes/no)
Degree of reflux
Analysis: Multivariable logistic regression

10. 628 Children with First UTI
Results
74,974 Children 0-6 years of age with at least 2 clinic visits
719 Children with any Urinary Tract Infection
First UTI incidence rate: per person-year
628 Children with First UTI
611 Children with First UTI and not Excluded
Recurrent UTI incidence rate: per person-year
83 Children with Recurrent UTI

11. Observation time
Mean observation time was 408 days with a median of 310 days (IQR 150 – 584 days), range of days

12. First and Recurrent UTI
First UTI (Number, %)
Recurrent UTI (Number, %)
Total
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)
Age
Less than 2 years
2 - 6 years
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)
In terms of males, 32 (47%) did not have circumcision status documented. Of the 26 uncirc males, 5 had recurrences (19%) versus 0/10 circumcised males.

13. 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 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)
Explain this is first aim, time to event – recurrent UTI. HR 2.75 in 3-4 yr olds. HR for 2-6 yr combined 2.01 (sig)
1 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

14. Time To Recurrent UTI by Age24 36
Observation Time (months)
Age < 2 Years
Age ≥ 2 – 6 Years 12
100 75
Percent without Recurrence 50 25

15. 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 )
When considering antibiotic prophylaxis, there is concern of confounding by indication (i.e. that child more likely to have recurrence is more likely to get prophylaxis). Propensity score analysis is one way to attempt to adjust for potential confounding by indication

16. 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)
0.212
0.07 – 0.63
Age
- Less than 2 years
2 – 6 years
21 (80.8)
30 (52.6)
0.263
0.09 – 0.80
VCUG
- Normal
Not Performed
VUR Grade 1-3
- VUR Grade 4-5
14 (70.0)
27 (51.9)
3 (100.0)
0.46
3.00 NA
0.15 – 1.39
0.30 – 30.02
Antibiotic prophylaxis
- None
- Exposed to prophylaxis
34 (53.1)
17 (89.5)
7.502
1.60 – 35.17
This is 2nd aim – resistance among recurrent UTI subjects. First column shows # of resistant infections and % of recurrent UTIs that were resistant among that group. Proph 7.5X the risk of resistant infection. Persisted when control for propensity score and whether first uTI was resistant
1 Odds ratio of resistant versus pan-sensitive organism as cause of recurrent UTI
2 p ≤ 0.01
3 p < 0.05

17. Probability of Recurrent UTI Being Antibiotic Resistant1
Prophylactic Antibiotic exposure
Non-Caucasian
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
Because prophylaxis is highly correlated with age < 2 yrs and VUR given the AAP recommendation. We developed a predicted probability of resistance from MV model for the following 4 exposures.
1 For each exposure variable, a “+” represents that exposure being present
2 Probability of causative organism being resistant to any antibiotic

18. 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 3-5, and Caucasian children had an increased risk of recurrent UTI
VUR Grade 1-3 had no significant effect on recurrence risk

19. 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

20. 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

21. 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

22. 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

23. 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
On bullet 3, esp lower grade VUR

24. 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

25. 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)
Such as first time seizure

26. 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

27. 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)
In terms of males, 32 (47%) did not have circumcision status documented. Of the 26 uncirc males, 5 had recurrences (19%) versus 0/10 circumcised males.
1 Differences were not statistically significant

28. Effect of Antibiotic Prophylaxis Stratified by VUR Status1
Hazard Ratio for Antibiotic Prophylaxis2 (95% CI)
VCUG
- Normal
Not Performed
VUR Present
0.27 (0.04 – 2.02)
1.44 (0.57 – 3.64)
0.95 (0.29 – 3.13)
Explain this is first aim, time to event – recurrent UTI.
1 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

29. Risk of Recurrent UTI in Females1
Multivariable Hazard Ratio2 (95% CI)
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)
Explain this is first aim, time to event – recurrent UTI.
1 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

30. Risk of Recurrent UTI in Males1
Multivariable Hazard Ratio2 (95% CI)
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)
Explain this is first aim, time to event – recurrent UTI.
1 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

31. Risk of Recurrent UTI by 1 Year Age Groups1
Multivariable Hazard Ratio2 (95% CI)
Gender (Ref. Male)
- Female
1.08 (0.51 – 1.96)
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
0.97 (0.48 – 1.96)
Explain this is first aim, time to event – recurrent UTI.
1 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

32. 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
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

33. 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

34. 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

35. 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)