Unanswered Questions and Unquestioned Answers TM Prepared for your next patient. AAP Guideline for the Diagnosis and Management of UTIs in Febrile Infants Unanswered Questions and Unquestioned Answers Kenneth B. Roberts, MD, FAAP Professor of Pediatrics (Emeritus) University of North Carolina Welcome slide for use during audience walk-in.

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AAP 2011 Clinical Practice Guideline Diagnosis and Management of the Initial UTI in Febrile Infants and Children, 2 to 24 Months* *Guideline: Pediatrics. 2011;128(3):595–610 Technical report: Pediatrics. 2011;128(3):e749–e770

Revision of 1999 Guideline Routine for American Academy of Pediatrics (AAP) to revise guidelines New evidence since 1999 New explicit reporting format “Recommendations” now “Action Statements” Aggregate evidence quality Benefits Harms/risks/costs Benefit-harms assessment Value judgments Role of patient preferences Exclusions Intentional vagueness Policy level (strength of recommendation)

Preponderance of Benefit or Harm Balance of Benefit and Harm Evidence Quality Preponderance of Benefit or Harm Balance of Benefit and Harm A. Well-designed RCTs or diagnostic studies on relevant population Strong Recommendation B. RCTs or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies C. Observational studies (case-control and cohort design) Recommendation D. Expert opinion, case reports, reasoning from first principles Option No Recommendation Option Abbreviation: RCTs, randomized controlled trials.

Preponderance of Benefit or Harm Evidence Quality Preponderance of Benefit or Harm X. Exceptional situations where validating studies cannot be performed and there is a clear preponderance of benefit or harm Strong Recommendation Recommendation

AAP Subcommittee on Urinary Tract Infection (UTI) Stephen M. Downs, MD, MS: Epidemiology/informatics S. Maria E. Finnell, MD, MS: Epidemiology/informatics Stanley Hellerstein, MD: Pediatric nephrology Kenneth B. Roberts, MD, Chair: General pediatrics Linda D. Shortliffe, MD: Pediatric urology Ellen R. Wald, MD: Pediatric infectious diseases J. Michael Zerin, MD: Pediatric radiology Caryn Davidson, MA: AAP staff

Driving Force from the 1960s

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What’s New in This Revision Diagnosis Abnormal urinalysis as well as positive culture Positive culture = ≥50,000 colony-forming units (cfu)/mL Assessment of likelihood of UTI Treatment: Oral as effective as parenteral Imaging: Voiding cystourethrography (VCUG) not recommended routinely after first febrile UTI Follow-up: Emphasis on urine testing with subsequent febrile illnesses

Population Addressed Infants and young children, 2–24 months of age, with unexplained fever Rate of UTI: ~5% Rate of scarring: Higher than in older children

Population Addressed Infants and young children, 2–24 months of age, with unexplained fever Rate of UTI: ~5% Rate of scarring: Higher than in older children Excludes: <2 months of age Excludes: >24 months of age

Content Action Statements: 7 Diagnosis: 3 Treatment: 1 Imaging: 2 Follow-up: 1 Areas for Research: 8

Action Statement 1 If a clinician decides that a febrile infant with no apparent source for the fever requires antimicrobial therapy because of ill appearance or another pressing reason, a urine specimen should be obtained by catheterization for both culture and urinalysis before an antimicrobial is given. Evidence quality: A Strong recommendation

Methods of Collecting Specimen Suprapubic aspiration: “Gold standard,” but Variable success rates: 23–90% (higher with ultrasound guidance) Requires technical expertise and experience Often viewed as invasive More painful than catheterization May be no alternative in boys with severe phimosis or girls with tight labial adhesions

Methods of Collecting Specimen Bag urine Can’t avoid getting “vaginal wash” in girl or contamination in uncircumcised boy. Not suitable for culture. Negative culture rules out UTI, but Positive culture likely to be false-positive 88% false-positive overall 95% in boys 99% in circumcised boys Positive culture requires confirmation, which is not possible once antibiotic is started.

Methods of Collecting Specimen Catheterization Compared to suprapubic aspiration: Sensitivity = 95% Specificity = 99% Requires some skill, particularly in small infant girls. (Tip: If unsuccessful, leave catheter in.)

Action Statement 2 If a febrile infant is assessed as not requiring immediate antimicrobial therapy, then the likelihood of UTI should be assessed. If likelihood is low (<1%, <2%), it is reasonable to follow the child clinically. If the likelihood is not low, there are two options: Obtain specimen by catheter for culture and urinary analysis (UA). Obtain specimen by any means for UA and only culture those with positive UA.

Probability of UTI: Infant GIRLS Individual Factors Probability of UTI # of Factors Present Race: White Age: <12 months Temperature: ≥39⁰C Fever: ≥2 days Absence of another source of infection ≤1% No more than 1 ≤2% No more than 2

Probability of UTI: Infant BOYS Individual Factors Probability of UTI # of Factors Present Race: Nonblack Temperature: ≥39⁰C Fever: >24 hours Absence of another source of infection Circumcised No Yes ≤1% * No more than 2 ≤2% None No more than 3 *Probability of UTI exceeds 1% even with no risk factors other than being uncircumcised.

Action Statement 3 Diagnosis of UTI requires both: Positive culture ≥50,000 cfu/mL of uropathogen cultured from catheter specimen, AND Positive urinalysis Evidence quality: C Recommendation

Where Did 100,000 Come From? 0 100-1 101-2 102-3 103-4 104-5 105-6 >106 Kass E. Asymptomatic infections of the urinary tract. Trans Assoc Am Phys. 1956;69:56–64

Urinalysis Positive urinalysis required for diagnosis Positive Positive culture with “negative” urinalysis Contamination Asymptomatic bacteriuria Urinalysis not sensitive enough Positive Dipstick: +LE (leukocyte esterase) and/or +nitrite Microscopy: White blood cells ± bacteria

Action Statement 4 Choice of route: Initiating treatment orally or parenterally is equally efficacious, so choice is based on practical considerations. Evidence quality: A Strong recommendation

Action Statement 4 Choice of route: Initiating treatment orally or parenterally is equally efficacious, so choice is based on practical considerations. Evidence quality: A Strong recommendation Choice of drug: Based on local sensitivity patterns, adjusted according to sensitivity of particular uropathogen

Action Statement 4 Choice of route: Initiating treatment orally or parenterally is equally efficacious, so choice is based on practical considerations. Evidence quality: A Strong recommendation Choice of drug: Based on local sensitivity patterns, adjusted according to sensitivity of particular uropathogen Duration of treatment: 7–14 days Evidence quality: B Recommendation

Action Statement 5 Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS), Evidence quality: C Recommendation

Action Statement 5 Febrile infants with UTIs should undergo RBUS. Why: Evidence quality: C Recommendation Why: Yield of abnormal findings: 12–16% Permanent renal damage (1 year later) Sensitivity: 41% Specificity: 81% Actionable findings sufficient to warrant?

Action Statement 5 Febrile infants with UTIs should undergo RBUS. Evidence quality: C Recommendation When: Decide clinically: Within 48 hours if not responding to treatment as expected, unusually ill, or extenuating circumstances; otherwise, when convenient.

Action Statement 6 VCUG is not recommended to be performed routinely after the first febrile UTI if RBUS is normal. Evidence quality: B Recommendation

Vesico-Ureteral Reflux Law & Order Vesico-Ureteral Reflux

Action Statement 6 Garin EH, Olavarrio F, Garcia Nieto V, et al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized controlled study. Pediatrics. 2006;117(3):626–632 Pennesi M, Travan L, Peratoner L, et al. Is antibiotic prophylaxis in childrfen with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized controlled trial. Pediatrics. 2008;121(6):e1489–e1494 Montini G, Rigon L, Zuccheta P, et al. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008;122(5):1064–1071 Roussey-Kesler G, Gadjos V, Idres N, et al. Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux results from a prospective randomized study. J Urol. 2008;179(2):674–679 Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med. 2009;361(18):1748–1759 Brandström P, Esbjörner E, Herthelius M, et al. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. 2010;184(1):286–291

Action Statement 6 Reflux Grade N Prophylaxis No Prophylaxis P None # of Recurrences / Total N None 373 7 / 210 11 / 163 0.15 Grade I 72 2 / 37 2 / 35 1.00 Grade II 257 11 / 133 10 / 124 0.95 Grade III 285 31 / 140 40 / 145 0.29 Grade IV 104 16 / 55 21 / 49 0.14 1,091

Grade of Vesico-Ureteral Reflux (VUR) Recurrence Rate of Febrile UTI By Reflux Grade, 1,091 Infants 2–24 Months NS NS NS NS NS Grade of Vesico-Ureteral Reflux (VUR)

Recurrence Rate of Febrile UTI By Reflux Grade, 1,091 Infants 2–24 Months NS NS NS NS NS (N=373) (N=100) (N=257) (N=285) (N=104) Grade of VUR

Action Statement 6 If RBUS is abnormal, VCUG may be part of additional imaging required to evaluate the abnormality. Evidence quality: B Recommendation Further evaluation should be conducted if there is a recurrence of febrile UTI. Evidence quality: X

Action Statement 6 Grade IV VUR 5 (5%) 1.2 (12%) Grade V VUR 1 (1%) After First UTI (N=100) After Recurrence (N=10) No VUR 65 (65%) 2.6 (26%) Grade I–III VUR 29 (29%) 5.6 (56%) Grade IV VUR 5 (5%) 1.2 (12%) Grade V VUR 1 (1%) 0.6 (6%)

Risk of Renal Scarring by Number of UTIs Action Statement 6 Risk of Renal Scarring by Number of UTIs Adapted from Jodul U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am. 1987;1(4):713–729

Impact of a More Restrictive Approach to Urinary Tract Imaging After Febrile Urinary Tract Infection “By restricting urinary tract imaging after an initial febrile UTI [based on NICE guidelines, 2007], rates of voiding cystourethrography and prophylactic antibiotic use decreased substantially without increasing the risk of UTI recurrence within 6 months and without an apparent decrease in detection of high-grade VUR.” Schroeder AR, Abidari JM, Kirpekar R, et al. Impact of a more restrictive approach to urinary tract imaging after febrile urinary tract infection. Arch Pediatr Adolesc Med. 2011;165(11):1027–1032

Childhood Urinary Tract Infections as a Cause of Chronic Kidney Disease “VUR with UTI without structural abnormalities in the kidneys seems not to cause CKD.” “Active treatment of VUR seems not to reduce the occurrence of CKD and, in large prospective follow-up studies, the renal function of patients with VUR has been well preserved.” Salo J, Ikäheimo R, Tapiainen T, et al. Childhood urinary tract infections as a cause of chronic kidney disease. Pediatrics. 2011;128(5):840–847

Action Statement 7 Following confirmation of UTI, parents or guardians should be instructed to seek prompt medical evaluation for future febrile illnesses to ensure that recurrent infections can be detected and treated promptly. Evidence quality: C Recommendation

Areas for Research (8) Relationship between UTIs and reduced renal function / hypertension Alternatives to invasive collection of urine and culture Role of VUR (and, thus, VCUG) Role of prophylaxis (Randomized Intervention for Children with Vesicoureteral Reflux [RIVUR] study) Genetics Hispanics Further treatment: What and for whom? Duration of treatment

Summary: What’s New . . . Diagnosis Abnormal urinalysis, as well as positive culture Positive culture = ≥50,000 cfu/mL Assessment of likelihood of UTI Treatment: Oral as effective as parenteral Imaging: VCUG not recommended routinely after first febrile UTI Follow-up: Emphasis on urine testing with subsequent febrile illnesses

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