UTI Update: Have We Been Led Astray? KAAP Sept 28, 2012 Robert Wittler, MD 1 Disclosure Neither I nor any member of my immediate family has a financial relationship or interest with any entity related to the content of this CME activity I do not intend to discuss an unapproved/ investigative use of a commercial product in my presentation 2 Objectives Understand criteria for the diagnosis of UTI Chose appropriate antimicrobial therapy Understand recommendations for imaging of patients diagnosed with UTI 3
AAP Clinical Practice Guideline Diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months no obvious neurologic or anatomic abnormality known to be associated with recurrent UTI or renal damage Pediatrics Sept 2011;128:595-610 Previous recommendation 1999 http://pediatrics.aappublications.org/content/ 128/3/595 4 AAP Clinical Practice Guideline Fever was defined as temperature of at least 38 C Lower and upper age limits were selected because studies on infants with unexplained fever generally have used those age limits and have documented that the prevalence of UTI is high ~5% Insufficient data to include older children 5 AAP Clinical Practice Guideline 7 recommendations (Action Statements) formulated Presented in the order in which a clinician would use them when evaluating and treating a febrile infant Diagnosis: 1-3 Management: 4-7 Intended to assist clinicians and not be the sole source of guidance 6
AAP Evidence Strengths Evidence Quality A. Well designed RCTs or diagnostic studies on relevant population B. RCTs or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies Preponderance of Benefit or Harm Strong Recommendation Balance of Benefit and Harm Option C. Observational studies (case-control and cohort design: Recommendation D. Expert opinion, case reports, reasoning from first principles Option No Recommendation X. Exceptional situations where validating studies cannot be performed and there is clear preponderance of benefit or harm Recommendation Strong Recommendation 7 Action Statement 1 If it is decided that a febrile infant with no apparent source requires antimicrobial therapy because of ill appearance or another pressing reason, then Ensure that a urine specimen is obtained for both culture and urinalysis prior to an antimicrobial being administered Catheterization or suprapubic aspiration (SPA) Evidence quality: A; strong recommendation 8 Action Statement 2 If a febrile infant with no apparent source is assessed as not being so ill to require immediate antimicrobial therapy, then the clinician should assess the liklihood of UTI 9
Action Statement 2a Low liklihood of UTI Clinical follow-up and monitoring without testing is sufficient Evidence quality: A; strong recommendation 10 Risk Factors: Girls White race Age <12 mo Temperature 39 C Fever 2 days Absence of another source of infection 11 Girls Probability of UTI No. of Factors Present 1% No more than 1 2% No more than 2 12
Risk Factors: Boys Nonblack race Temperature 39 C Fever >24 hours Absence of another source of infection 13 Boys Probability of UTI No. of Factors Present Uncircumcised Circumcised 1% a No more than 2 2% None No more than 3 a Probability of UTI exceeds 1% even with no risk factors other than being uncircumcised 14 Action Statement 2b If not felt to be in a low-risk group there are 2 choices 1. Cath or SPA urine specimen for culture and urinalysis 2. Bag specimen for urinalysis (don t culture) If suggestive of UTI (pos. leukocyte esterase or nitrite or microscopic pos. for leukocytes or bacteria), then obtain cath or SPA for culture If LE and nitrite are negative on fresh (<1 hour since void) urine, then it is reasonable to monitor recognizing that negative urinalysis results do not rule out UTI with certainty 15
Action Statement 3 Diagnosis of UTI should require both 1. Urinalysis results that suggest infection pyuria and/or bacteruria 2. Culture at least 50,000 cfu/ml of a single uropathogen from a cath or SPA specimen Evidence quality: C; recommendation 16 Microscopic Analysis for Bacteruria Presence of bacteria in a fresh, Gram-stained specimen of uncentrifuged urine correlates with 10 5 cfu/ml in culture An enhanced urinalysis combining the counting chamber assessment of pyuria with Gram staining of uncentrifuged urine, with a threshold of at least one Gram-negative rod in 10 oil immersion fields, has greater sensitivity, specificity, and positive predictive value than does standard urinalysis 1 and is the preferred method of urinalysis 1 Hoberman et al, Pediatr Infect Dis J 1996;15:304-309 17 Test Leukocyte Esterase (LE) Sensitivity (Range), % Specificity (Range), % 83 (67-94) 78 (64-92) Nitrite 53 (15-82) 98 (90-100) LE or Nitrite pos. 93 (90-100) 72 (58-91) Microscopy, WBCs 73 (32-100) 81 (45-98) Microscopy, bacteria 81 (16-99) 83 (11-100) LE, nitrite, or microscopy positive 99.8 (99-100) 70 (60-92) 18
Pyuria The absence of pyuria in children with true UTIs is rare Positive culture without pyuria contaminated specimen asymptomatic bacteruria insensitive criteria for pyuria 19 Assessing Pyuria Standard method has been centrifugation of urine and microscopic analysis with a threshold of 5 WBCs per high-power field ~25 WBCs per µl If a counting chamber is used, the finding of at least 10 WBCs per µl in uncentrifuged urine has been demonstrated to be more sensitive 1 and performs well in clinical situations in which the standard method does not, such as with very young infants 2 1 Hoberman et al, Pediatr Infect Dis J 1996;15:304-309 2 Herr et al, Pediatrics 2001;108:866-871 20 Action Statement 4a The clinician should base the choice of route of antibiotic administration on practical considerations Treatment orally or parenterally is equally efficacious Choice of antibiotic should be based on local susceptibilities and adjusted based on culture susceptibility results Evidence quality: A; strong recommendation 21
Empiric Oral Antimicrobial Agents Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole, sulfasoxazole Cefixime, cefpodoxime, cefprozil, cefuroxime axetil, cephalexin 22 Empiric IV Antimicrobial Agents Ceftriaxone Cefotaxime Ceftazidime Gentamicin Tobramycin Piperacillin 23 Oral vs IV for Initial Treatment Hoberman et al, Pediatrics 1999;104:79-86 Randomized multicenter clinical trial of oral cefixime (N=153) vs IV cefotaxime (N=153) in children age 1-24 months with febrile UTI With initial IV treatment subjects were changed to oral cefixime after 3 days or when afebrile for 24 hours, whichever was longer all received 14 days of treatment Repeat urine cultures were sterile within 24 hours in all children 24
Oral vs IV for Initial Treatment Mean time to defervescence was 24.7 hours and 23.9 hours for oral and IV treatment respectively (P=.76) Symptomatic reinfections occurred in 4.6% of children treated orally and 7.2% of children treated IV (P=.28) New renal scarring occurred in 9.8% with oral and 7.2% with IV treatment (P=.21) Mean costs were at least twofold higher for children treated IV 25 Oral vs IV for Initial Treatment 13 (4.3%) had a positive blood culture clinically indistinguishable from children with a negative blood culture all (5 oral, 8 IV) had a repeat blood culture performed within 24 hours that was sterile 26 Action Statement 4b Duration of therapy 7-14 days Evidence quality: B; recommendation 27
Action Statement 5 Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS) Evidence quality: C; recommendation 28 Action Statement 6a VCUG should not be performed routinely VCIG is indicated if RBUS reveals hydronephrosis scarring or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as other atypical or complex clinical circumstances Evidence quality: B; recommendation 29 Rationale There are a significant number of infants who develop pyelonephritis in whom VUR cannot be demonstrated Effectiveness of antimicrobial prophylaxis for patients who have VUR has been challenged several studies have suggested that prophylaxis does not prevent recurrent febrile UTI* National study currently in progress *Pennesi et al, Pediatrics, 2008; Garin et al, Pediatrics, 2006; Montini et al, Pediatrics, 2008, Roussey-Kesler et al, J Urol, 2008; Craig et al, N Engl J Med, 2009 30
Recurrences of Febrile UTI/Pyelonephritis in Infants 2-24 Months With and Without Antimicrobial Prophylaxis by VUR Grade Reflux Grade Prophylaxis No Prophylaxis P # of Recurrences N # of Recurrences None 7 210 11 163 0.15 I 2 37 2 35 1.00 II 11 133 10 124 0.95 III 31 140 40 145 0.29 N IV 16 55 21 49 0.14 31 No VUR 32 Grade I VUR 33
Grade II VUR 34 Grade III VUR 35 Grade IV VUR 36
Rates of VUR in a Hypothetical Cohort of Infants After First UTI and After Recurrence VUR Grade After First UTI (N=100) Rate, % After Recurrence (N=100) None 65 26 Grades 1-11I 29 56 Grade IV 5 12 Grade V 1 6 37 Renal Scarring in Relationship to Episodes of Pyelonephritis 60% 58% Risk of renal scarring 45% 30% 35% 15% 15% 9% 0% 1 2 3 4 Number of bouts of pyelonephritis Jodal U, Infect Dis Clin North Am 1987;1:713-729 38 Action Statement 6b Further evaluation should be conducted if there is recurrence of febrile UTI VCUG Evidence quality: X; recommendation 39
Action Statement 7 After confirmation of UTI, the clinician should instruct parents or guardians to seek prompt medical evaluation (ideally within 48 hours) for future febrile illnesses to ensure that recurrent infections can be detected and treated promptly Evidence quality: C; recommendation 40 AAP Section on Urology Response Pediatrics April 2012;129:e1054-e1056 Disagree with the recommendation not to do a VCUG after the first febrile UTI if the ultrasound is normal Effect of this new approach is unknown as it has not been studied 41 42
Length of IV Treatment in Young Infants Brady et al, Pediatrics 2010;126:196-203 Retrospective cohort of infants <6 months of age hospitalized with UTIs between 1999 and 2004 at 24 children s hospitals 12,333 children Goal was to determine the association between short-duration ( 3 days) and long-duration IV antibiotic therapy and treatment failure treatment failure defined as readmission within 30 days 43 Multivariate Adusted Odds Ratios for Treatment Failure Age OR (95% CI) <1 mo Reference 1 mo and <2 mo 1.10 (0.73-1.66) 2 mo and <3 mo 0.83 (0.54-1.28) 3 mo and <4 mo 0.86 (0.51-1.45) 4 mo and <5 mo 1.25 (0.61-2.57) 5 mo and <6 mo 1.37 (0.81-2.32) 44 Multivariate Adusted Odds Ratios for Treatment Failure Bacteremia OR (95% CI) Known 1.90 (0.45-8.14) Unknown or not present Reference 45
Multivariate Adusted Odds Ratios for Treatment Failure Length of IV Antibiotic Therapy OR (95% CI) 3 days Reference 4 days 1.02 (0.77-1.35) 46 Length of IV Treatment in Young Infants Treatment failure rates were 1.6% for children who received short-course IV antibiotic therapy and 2.2% for those who received long-course therapy Known presence of genitourinary tract abnormalities was associated with higher rate of readmission 4.5% vs 1.5%; OR 1.83 (1.20-2.79) 47
APPENDIX Clinical practice guideline algorithm.