recurrent urinary tract infections: risk factors and effectiveness of prophylaxis in a primary care...

Recurrent Urinary Tract Infections: Recurrent Urinary Tract Infections: Risk Factors and Effectiveness of Risk Factors and Effectiveness of

Prophylaxis in a Primary Care CohortProphylaxis in a Primary Care Cohort

AcademyHealth Annual MeetingAcademyHealth Annual Meeting

Patrick H. Conway, MD, MScPatrick H. Conway, MD, MScAvital Cnaan, PhDAvital Cnaan, PhD

Theoklis Zaoutis, MD, MSCETheoklis Zaoutis, MD, MSCEBrandon Henry, BSBrandon Henry, BS

Robert Grundmeier, MDRobert Grundmeier, MDRon Keren, MD, MPHRon Keren, MD, MPH

EpidemiologyEpidemiology

Urinary tract infection (UTI) is the most Urinary tract infection (UTI) is the most common serious bacterial infection in common serious bacterial infection in children children

Estimates of cumulative incidence in Estimates of cumulative incidence in children 0 - 6 years suggest 70,000 to 180,000 children 0 - 6 years suggest 70,000 to 180,000 of the annual U.S. birth cohort will have a UTI of the annual U.S. birth cohort will have a UTI by age sixby age six

Little data on recurrent UTI rate but previous Little data on recurrent UTI rate but previous estimates of 20 - 48% within 6-12 months estimates of 20 - 48% within 6-12 months

Traditional Conceptual ModelTraditional Conceptual Model

UTI(s)

VUR

RENALSCARRING

End Stage Renal Disease

Pre-eclampsia

Hypertension

Prophylactic antibiotics prevent recurrent UTI

Surgery corrects VUR

Figure 1 Conceptual Model

ControversyControversy

Cochrane report summarized that Cochrane report summarized that evidence “to support widespread use evidence “to support widespread use of antibiotics to prevent recurrent UTI of antibiotics to prevent recurrent UTI is weak” is weak”

Two small clinical trials found Two small clinical trials found prophylaxis had no significant effect on prophylaxis had no significant effect on risk of recurrent UTI or renal scarringrisk of recurrent UTI or renal scarring

Specific Aims Specific Aims

1.1. To determine the factors associated with To determine the factors associated with risk of recurrent UTI in a primary-care risk of recurrent UTI in a primary-care based cohort and to estimate the risk based cohort and to estimate the risk reduction provided by prophylactic reduction provided by prophylactic antibiotics antibiotics

2.2. To determine the risk factors for antibiotic To determine the risk factors for antibiotic resistance among recurrent UTIsresistance among recurrent UTIs

Methods: Data SourceMethods: Data Source

Data obtained from primary care based Data obtained from primary care based network of practices who contribute to network of practices who contribute to CHOP’s Epic electronic health recordCHOP’s Epic electronic health record

27 practices from urban, suburban, and 27 practices from urban, suburban, and semi-rural areas in 3 statessemi-rural areas in 3 states

Data contains laboratory, prescription, Data contains laboratory, prescription, and radiology data from clinic and and radiology data from clinic and emergency room settingsemergency room settings

Cohort Inclusion CriteriaCohort Inclusion Criteria Identified children 0 - 6 years of age with at Identified children 0 - 6 years of age with at

least 2 office visits between 7/1/2001 and least 2 office visits between 7/1/2001 and 5/31/2006 5/31/2006

From these infants, identified cohort with From these infants, identified cohort with first UTI based on positive urine culture first UTI based on positive urine culture (>50,000 CFU/ml single organism)(>50,000 CFU/ml single organism)

Followed infants until last documented Followed infants until last documented contact with the network or until they contact with the network or until they experienced the primary outcome, a experienced the primary outcome, a recurrent UTIrecurrent UTI

Aim 1Aim 1 Design: CohortDesign: Cohort Outcome variable: Time to recurrent UTI Outcome variable: Time to recurrent UTI Covariates:Covariates:

Age at first UTIAge at first UTIGenderGenderRaceRaceDegree of reflux Degree of reflux Antibiotic prophylaxis Antibiotic prophylaxis

Antibiotic prophylaxis was considered as a Antibiotic prophylaxis was considered as a time varying covariate time varying covariate

Analysis: Cox survival time regression Analysis: Cox survival time regression

Aim 2Aim 2 Design: Nested case-controlDesign: Nested case-control Outcome variable: Resistant versus pan-Outcome variable: Resistant versus pan-

sensitive recurrent infections sensitive recurrent infections Covariates:Covariates:

Age at first UTIAge at first UTIGenderGenderRaceRaceAntibiotic prophylaxis exposure (yes/no)Antibiotic prophylaxis exposure (yes/no)Degree of reflux Degree of reflux

Analysis: Multivariable logistic regression Analysis: Multivariable logistic regression

ResultsResults

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

First UTI incidence rate: 0.007 per person-year

83 Children with Recurrent UTI

Recurrent UTI incidence rate: 0.12 per person-year

Observation timeObservation time

Mean observation time was 408 days Mean observation time was 408 days with a median of 310 days (IQR 150 – with a median of 310 days (IQR 150 – 584 days), range of 24 - 1600 days584 days), range of 24 - 1600 days

First and Recurrent UTIFirst 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)

Risk of Recurrent UTIRisk of Recurrent UTI11

1 Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care network2 Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure3 p<0.014 p<0.055 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed and intermittent nature of exposure

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)

Time To Recurrent UTI by AgeTime To Recurrent UTI by Age

0

0 24 36

Observation Time (months)

Age < 2 Years Age ≥ 2 – 6 Years

12

100

75

50

25

Pe

rce

nt w

itho

ut R

ecu

rren

ce

Antibiotic Prophylaxis Antibiotic Prophylaxis Propensity Score AnalysisPropensity Score Analysis

Developed a propensity score for likelihood of Developed a propensity score for likelihood of receipt of prophylactic antibiotics receipt of prophylactic antibiotics

Analyses stratified by propensity score Analyses stratified by propensity score quintile demonstrated no significant effect of quintile demonstrated no significant effect of antibiotic prophylaxisantibiotic prophylaxis

Antibiotic prophylaxis still did not decrease Antibiotic prophylaxis still did not decrease risk of recurrent UTI when controlling for:risk of recurrent UTI when controlling for:• Propensity quintile (HR 1.03, 0.51 – 2.08Propensity quintile (HR 1.03, 0.51 – 2.08 ))• Continuous propensity score (HR 1.02, 0.51 – 2.05 ) Continuous propensity score (HR 1.02, 0.51 – 2.05 )

Risk of Antibiotic Resistance among Recurrent UTI SubjectsRisk of Antibiotic Resistance among Recurrent UTI Subjects

1 Odds ratio of resistant versus pan-sensitive organism as cause of recurrent UTI2 p ≤ 0.013 p < 0.05

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)

Ref0.20 0.02 – 1.73

Race - Non-Caucasian- Caucasian

24 (82.8)27 (50.0)

Ref0.212 0.07 – 0.63

Age- Less than 2 years- 2 – 6 years

21 (80.8)30 (52.6)

Ref0.263 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)

Ref0.463.00NA

0.15 – 1.390.30 – 30.02

NA

Antibiotic prophylaxis- None- Exposed to prophylaxis

34 (53.1)17 (89.5)

Ref7.502 1.60 – 35.17

Probability of Recurrent UTI Being Antibiotic ResistantProbability of Recurrent UTI Being Antibiotic Resistant11

1 For each exposure variable, a “+” represents that exposure being present2 Probability of causative organism being resistant to any antibiotic

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

SummarySummary

Incidence rate for recurrent UTI of 12% per Incidence rate for recurrent UTI of 12% per year is significantly lower than previous year is significantly lower than previous estimatesestimates

Prophylactic antibiotics not associated with Prophylactic antibiotics not associated with decreased risk of recurrent UTI but decreased risk of recurrent UTI but significantly associated with increased the significantly associated with increased the risk of resistant infectionsrisk of resistant infections

Older 2-6 year old children, especially age 3-Older 2-6 year old children, especially age 3-5, and Caucasian children had an increased 5, and Caucasian children had an increased risk of recurrent UTI risk of recurrent UTI

VUR Grade 1-3 had no significant effect on VUR Grade 1-3 had no significant effect on recurrence riskrecurrence risk

Limitations – Antibiotic exposureLimitations – Antibiotic exposure

Antibiotic exposure was based on Antibiotic exposure was based on prescription data prescription data

Likely overestimates the exposure in Likely overestimates the exposure in both subjects with and without both subjects with and without recurrent UTIrecurrent UTI

Potential confounding by indication Potential confounding by indication and residual unobservable and residual unobservable confoundingconfounding

Limitations – Sparse or Missing DataLimitations – Sparse or Missing Data

Missing data due to VCUG not being Missing data due to VCUG not being performedperformed

Possibility of missing data from Possibility of missing data from outside networkoutside network

• Attempted to minimize through chart Attempted to minimize through chart review including correspondence review including correspondence from outside hospitals and clinics from outside hospitals and clinics

StrengthsStrengths

Based on primary care populationBased on primary care population Cohort design with large sample size that Cohort design with large sample size that

followed subjects for on average over 1 year followed subjects for on average over 1 year in “natural experiment” in “natural experiment”

Concurrently investigates potential risks Concurrently investigates potential risks and benefits of prophylactic antibiotics in and benefits of prophylactic antibiotics in same cohortsame cohort

Implications – Antibiotic ProphylaxisImplications – Antibiotic Prophylaxis

Given potential lack of prevention benefit and Given potential lack of prevention benefit and demonstrated harm due to resistant demonstrated harm due to resistant infections, this study in combination with infections, this study in combination with other negative RCTs raises doubts about the other negative RCTs raises doubts about the effectiveness of prophylactic antibioticseffectiveness of prophylactic antibiotics

Close monitoring without prophylaxis after Close monitoring without prophylaxis after first UTI may be a reasonable management first UTI may be a reasonable management strategystrategy

Implications - VUR and Antibiotic ProphylaxisImplications - VUR and Antibiotic Prophylaxis

Subjects with Grade 1-3 VUR had no Subjects with Grade 1-3 VUR had no significant increased risk of recurrence and significant increased risk of recurrence and Grade 4-5 VUR had increased recurrence risk Grade 4-5 VUR had increased recurrence risk

Antibiotic prophylaxis did not effect the risk Antibiotic prophylaxis did not effect the risk of recurrence in either group in stratified or of recurrence in either group in stratified or multivariable analysismultivariable analysis

Unclear if VUR, especially lower grade VUR, Unclear if VUR, especially lower grade VUR, should be sole factor considered in should be sole factor considered in prophylaxis recommendationsprophylaxis recommendations

Implications – Other Risk FactorsImplications – Other Risk Factors

Non-Caucasians had decreased risk of Non-Caucasians had decreased risk of recurrence but increased risk of recurrence but increased risk of resistant infectionsresistant infections

Older children (age 2-6 years) had Older children (age 2-6 years) had increased risk of recurrence; this may increased risk of recurrence; this may represent dysfunctional elimination represent dysfunctional elimination syndromessyndromes

Next Steps and ConsiderationsNext Steps and Considerations

RCT of antibiotic prophylaxis versus close RCT of antibiotic prophylaxis versus close monitoring monitoring

Should UTI be considered as 2 hits Should UTI be considered as 2 hits necessary prior to long-term treatment? necessary prior to long-term treatment? • Child with first UTI and no major urinary tract Child with first UTI and no major urinary tract

anomalies watched closely off treatment anomalies watched closely off treatment

Future studies should validate whether older Future studies should validate whether older age and Caucasian race are risk factors for age and Caucasian race are risk factors for recurrence and explore mechanisms (e.g. recurrence and explore mechanisms (e.g. dysfunctional elimination, genetic markers)dysfunctional elimination, genetic markers)

AcknowledgmentsAcknowledgments

University of Pennsylvania CERTS grantUniversity of Pennsylvania CERTS grant Dr. Ron KerenDr. Ron Keren Dr. Avital CnaanDr. Avital Cnaan Mr. Brandon Henry and Chris Bell, research Mr. Brandon Henry and Chris Bell, research

assistantsassistants University of Pennsylvania Clinical Scholars University of Pennsylvania Clinical Scholars

ProgramProgram Practice-Based Research Network at CHOP, Practice-Based Research Network at CHOP,

its physicians, staff, and patientsits physicians, staff, and patients

Males by Circumcision StatusMales 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 Effect of Antibiotic Prophylaxis Stratified by VUR Statusby VUR Status11

1 Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care network2 Antibiotic prophylaxis exposure was modeled as time varying covariate in order to take into account total time exposed and intermittent nature of exposure

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)

Risk of Recurrent UTI in FemalesRisk of Recurrent UTI in Females11


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)


Risk of Recurrent UTI in MalesRisk of Recurrent UTI in Males11


Race (Ref. Non-Caucasian) - Caucasian 0.59 (.10 – 3.74)

Age (Ref. Less than 2 years)- 2 - 6 years 2.30 (.48 – 11.1)


1.24 (0.19 – 8.21)1.36 (0.48 – 11.1)16.1 (1.91 – 136)



Risk of Recurrent UTI by 1 Year Age GroupsRisk of Recurrent UTI by 1 Year Age Groups11


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)


0.68 (0.39 – 1.21)1.14 (0.47 – 2.82)

4.38 (1.25 – 15.29)4


1 Time-to-event performed from date of first UTI until event, recurrent UTI, or last clinic visit within the primary care network2 Multivariable survival analysis controlling for gender, race, age, VCUG result, and prophylactic antibiotic exposure3 p<0.014 p<0.05

Other Recurrent UTI Studies Other Recurrent UTI Studies

Winberg studies published in ‘73 and ‘74 based Winberg studies published in ‘73 and ‘74 based on children 0-16 years who presented to on children 0-16 years who presented to Children’s Hospital in Goteborg from 1960-66Children’s Hospital in Goteborg from 1960-66

Proposed it was population based as “few other Proposed it was population based as “few other clinics” in the areaclinics” in the area

After first UTI, children had urine tested at 13, 30, After first UTI, children had urine tested at 13, 30, 60, and 90 days after first UTI and then at 1, 3, and 60, and 90 days after first UTI and then at 1, 3, and 5 years after first UTI (not necessarily based on 5 years after first UTI (not necessarily based on symptoms)symptoms)

Recurrence rate of 29% overallRecurrence rate of 29% overall Decreasing “recurrence” rate with boys over time Decreasing “recurrence” rate with boys over time

but no comment on circumcision status of malesbut no comment on circumcision status of males

Other Recurrent UTI Studies Other Recurrent UTI Studies (cont)(cont)

Panaretto et al (J Paed Child Health 99)Panaretto et al (J Paed Child Health 99)• 290 children 0-5 years diagnosed with UTI 290 children 0-5 years diagnosed with UTI

in ED, then had follow-up with 261 that in ED, then had follow-up with 261 that consisted of phone call to parents at 6 and consisted of phone call to parents at 6 and 12 months after UTI12 months after UTI

• If parents reported UTI recurrence, then If parents reported UTI recurrence, then investigators attempted to confirm via investigators attempted to confirm via cultureculture

• Found 13% recurrence rateFound 13% recurrence rate

Other Recurrent UTI Studies Other Recurrent UTI Studies (cont)(cont)

Garin et al 2006 demonstrated no significant Garin et al 2006 demonstrated no significant different recurrence risk in prophylaxis different recurrence risk in prophylaxis group versus no prophylaxis group (17 vs group versus no prophylaxis group (17 vs 23% overall) 23% overall)

9% pyelonephritis in prophylaxis group 9% pyelonephritis in prophylaxis group versus 3% in no prophylaxis groupversus 3% in no prophylaxis group

Among children on prophylaxis, recurrence Among children on prophylaxis, recurrence rate of 8.8% for subjects without VUR versus rate of 8.8% for subjects without VUR versus 23.6% for those with VUR23.6% for those with VUR

Cochrane ReviewCochrane Review

• Trials by Savage, Smellie, Stansfield in Trials by Savage, Smellie, Stansfield in 70’s of prophylaxis versus placebo70’s of prophylaxis versus placebo

• Often included children with multiple Often included children with multiple previous UTIs, no blinding, and testing of previous UTIs, no blinding, and testing of urine without symptomsurine without symptoms

• Recurrence rate as high as 69% in control Recurrence rate as high as 69% in control arm (savage)arm (savage)

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