Recurrent Urinary Tract Infections: Risk Factors and Effectiveness of Prophylaxis in a Primary Care Cohort AcademyHealth

1. Recurrent Urinary Tract Infections: Risk Factors and Effectiveness of Prophylaxis in a Primary Care CohortAcademyHealth 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 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

3. Figure 1 Conceptual Model Prophylactic End Stage Renal antibioticsprevent Disease recurrentUTI UTI ( s ) RENAL Hypertension SCARRING VUR Surgery Pre - eclampsia corrects VUR Traditional Conceptual Model

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 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

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

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. 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: 0.007 per person-year 628 Children with First UTI 611 Children with First UTI and not Excluded Recurrent UTI incidence rate: 0.12 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 24 - 1600 days

12. First and Recurrent UTI

13. Risk of Recurrent UTI1 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. 0 0 12 24 36 Observation Time (months) Age < 2 Years Age ≥ 2 – 6 Years Time To Recurrent UTI by Age 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 )

16. Risk of Antibiotic Resistance among Recurrent UTI Subjects 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 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

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)

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 1 Differences were not statistically significant

28. Effect of Antibiotic Prophylaxis Stratified by VUR Status1 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 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 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 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 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

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)