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

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 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

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

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

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

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: 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

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, %) 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.

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) 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

Time To Recurrent UTI by Age 24 36 Observation Time (months) Age < 2 Years Age ≥ 2 – 6 Years 12 100 75 Percent without Recurrence 50 25

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

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

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

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

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 On bullet 3, esp lower grade VUR

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) Such as first time seizure

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) 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

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

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

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

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

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)