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Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and
Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months
   SUBCOMMITTEE ON URINARY TRACT INFECTION and STEERING
   COMMITTEE ON QUALITY IMPROVEMENT AND MANAGEMENT
          Pediatrics; originally published online August 28, 2011;
                        DOI: 10.1542/peds.2011-1330



 The online version of this article, along with updated information and services, is
                        located on the World Wide Web at:
   http://pediatrics.aappublications.org/content/early/2011/08/24/peds.2011-1330




  PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
  publication, it has been published continuously since 1948. PEDIATRICS is owned,
  published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
  Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy
  of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.




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FROM THE AMERICAN ACADEMY OF PEDIATRICS




CLINICAL PRACTICE GUIDELINE

Urinary Tract Infection: Clinical Practice Guideline for
the Diagnosis and Management of the Initial UTI in
Febrile Infants and Children 2 to 24 Months
SUBCOMMITTEE ON URINARY TRACT INFECTION, STEERING
COMMITTEE ON QUALITY IMPROVEMENT AND MANAGEMENT                     abstract
KEY WORDS
urinary tract infection, infants, children, vesicoureteral reflux,
                                                                    OBJECTIVE: To revise the American Academy of Pediatrics practice
voiding cystourethrography                                          parameter regarding the diagnosis and management of initial urinary
ABBREVIATIONS                                                       tract infections (UTIs) in febrile infants and young children.
SPA—suprapubic aspiration                                           METHODS: Analysis of the medical literature published since the last
AAP—American Academy of Pediatrics
UTI—urinary tract infection
                                                                    version of the guideline was supplemented by analysis of data provided
RCT—randomized controlled trial                                     by authors of recent publications. The strength of evidence supporting
CFU—colony-forming unit                                             each recommendation and the strength of the recommendation were
VUR—vesicoureteral reflux
WBC—white blood cell
                                                                    assessed and graded.
RBUS—renal and bladder ultrasonography                              RESULTS: Diagnosis is made on the basis of the presence of both
VCUG—voiding cystourethrography
                                                                    pyuria and at least 50 000 colonies per mL of a single uropathogenic
This document is copyrighted and is property of the American        organism in an appropriately collected specimen of urine. After 7 to 14
Academy of Pediatrics and its Board of Directors. All authors
have filed conflict of interest statements with the American          days of antimicrobial treatment, close clinical follow-up monitoring
Academy of Pediatrics. Any conflicts have been resolved through      should be maintained to permit prompt diagnosis and treatment of
a process approved by the Board of Directors. The American          recurrent infections. Ultrasonography of the kidneys and bladder
Academy of Pediatrics has neither solicited nor accepted any
commercial involvement in the development of the content of
                                                                    should be performed to detect anatomic abnormalities. Data from the
this publication.                                                   most recent 6 studies do not support the use of antimicrobial prophy-
The recommendations in this report do not indicate an exclusive     laxis to prevent febrile recurrent UTI in infants without vesicoureteral
course of treatment or serve as a standard of medical care.         reflux (VUR) or with grade I to IV VUR. Therefore, a voiding cystoure-
Variations, taking into account individual circumstances, may be    thrography (VCUG) is not recommended routinely after the first UTI;
appropriate.
                                                                    VCUG is indicated if renal and bladder ultrasonography reveals hydro-
All clinical practice guidelines from the American Academy of
Pediatrics automatically expire 5 years after publication unless
                                                                    nephrosis, scarring, or other findings that would suggest either high-
reaffirmed, revised, or retired at or before that time.              grade VUR or obstructive uropathy and in other atypical or complex
                                                                    clinical circumstances. VCUG should also be performed if there is a
                                                                    recurrence of a febrile UTI. The recommendations in this guideline do
                                                                    not indicate an exclusive course of treatment or serve as a standard of
                                                                    care; variations may be appropriate. Recommendations about antimi-
                                                                    crobial prophylaxis and implications for performance of VCUG are
                                                                    based on currently available evidence. As with all American Academy of
                                                                    Pediatrics clinical guidelines, the recommendations will be reviewed
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1330                   routinely and incorporate new evidence, such as data from the Ran-
doi:10.1542/peds.2011-1330
                                                                    domized Intervention for Children With Vesicoureteral Reflux (RIVUR)
                                                                    study.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2011 by the American Academy of Pediatrics              CONCLUSIONS: Changes in this revision include criteria for the diag-
COMPANION PAPERS: Companions to this article can be found
                                                                    nosis of UTI and recommendations for imaging. Pediatrics 2011;128:
on pages 572 and e749, and online at www.pediatrics.org/cgi/        595–610
doi/10.1542/peds.2011-1818 and www.pediatrics.org/cgi/doi/10.
1542/peds.2011-1332.



PEDIATRICS Volume 128, Number 3, September 2011                                                                                          595
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INTRODUCTION                                     for use in a variety of clinical settings    ness of prophylactic antimicrobial
Since the early 1970s, occult bactere-           (eg, office, emergency department, or         therapy to prevent recurrence of fe-
mia has been the major focus of con-             hospital) by clinicians who treat in-        brile UTI/pyelonephritis in children
cern for clinicians evaluating febrile           fants and young children. This text is a     with vesicoureteral reflux (VUR). The
infants who have no recognizable                 summary of the analysis. The data on         latter was based on the new and grow-
source of infection. With the introduc-          which the recommendations are                ing body of evidence questioning the
tion of effective conjugate vaccines             based are included in a companion            effectiveness of antimicrobial prophy-
against Haemophilus influenzae type               technical report.4                           laxis to prevent recurrent febrile UTI in
b and Streptococcus pneumoniae                   Like the 1999 practice parameter, this       children with VUR. To explore this par-
(which have resulted in dramatic de-             revision focuses on the diagnosis and        ticular issue, the literature search was
creases in bacteremia and meningi-               management of initial urinary tract in-      expanded to include trials published
tis), there has been increasing appre-           fections (UTIs) in febrile infants and       since 1993 in which antimicrobial pro-
ciation of the urinary tract as the most         young children (2–24 months of age)          phylaxis was compared with no treat-
frequent site of occult and serious bac-         who have no obvious neurologic or an-        ment or placebo treatment for chil-
terial infections. Because the clinical          atomic abnormalities known to be as-         dren with VUR. Because all except 1 of
presentation tends to be nonspecific in           sociated with recurrent UTI or renal         the recent randomized controlled tri-
infants and reliable urine specimens             damage. (For simplicity, in the remain-      als (RCTs) of the effectiveness of pro-
for culture cannot be obtained without           der of this guideline the phrase “fe-        phylaxis included children more than
invasive methods (urethral cathe-                brile infants” is used to indicate febrile   24 months of age and some did not
terization or suprapubic aspiration              infants and young children 2–24              provide specific data according to
[SPA]), diagnosis and treatment may              months of age.) The lower and upper          grade of VUR, the authors of the 6 RCTs
be delayed. Most experimental and                age limits were selected because stud-       were contacted; all provided raw data
clinical data support the concept that           ies on infants with unexplained fever        from their studies specifically ad-
delays in the institution of appropriate         generally have used these age limits         dressing infants 2 to 24 months of age,
treatment of pyelonephritis increase             and have documented that the preva-          according to grade of VUR. Meta-
the risk of renal damage.1,2                     lence of UTI is high (ϳ5%) in this age       analysis of these data was performed.
This clinical practice guideline is a re-        group. In those studies, fever was de-       Results from the literature searches
vision of the practice parameter pub-            fined as temperature of at least 38.0°C       and meta-analyses were provided to
lished by the American Academy of                (Ն100.4°F); accordingly, this definition      committee members. Issues were
Pediatrics (AAP) in 1999.3 It was devel-         of fever is used in this guideline. Ne-      raised and discussed until consensus
oped by a subcommittee of the Steer-             onates and infants less than 2               was reached regarding recommenda-
ing Committee on Quality Improvement             months of age are excluded, because          tions. The quality of evidence support-
and Management that included physi-              there are special considerations in          ing each recommendation and the
cians with expertise in the fields of ac-         this age group that may limit the ap-        strength of the recommendation were
ademic general pediatrics, epidemiol-            plication of evidence derived from           assessed by the committee member
ogy and informatics, pediatric                   the studies of 2- to 24-month-old chil-      most experienced in informatics and
infectious diseases, pediatric nephrol-          dren. Data are insufficient to deter-         epidemiology and were graded ac-
ogy, pediatric practice, pediatric radi-         mine whether the evidence gener-             cording to AAP policy5 (Fig 1).
ology, and pediatric urology. The AAP            ated from studies of infants 2 to 24         The subcommittee formulated 7 rec-
funded the development of this guide-            months of age applies to children            ommendations, which are presented
line; none of the participants had any           more than 24 months of age.                  in the text in the order in which a clini-
financial conflicts of interest. The                                                            cian would use them when evaluating
guideline was reviewed by multiple               METHODS                                      and treating a febrile infant, as well as
groups within the AAP (7 committees, 1           To provide evidence for the guideline, 2     in algorithm form in the Appendix. This
council, and 9 sections) and 5 external          literature searches were conducted,          clinical practice guideline is not in-
organizations in the United States and           that is, a surveillance of Medline-listed    tended to be a sole source of guidance
Canada. The guideline will be reviewed           literature over the past 10 years for        for the treatment of febrile infants with
and/or revised in 5 years, unless new            significant changes since the guideline       UTIs. Rather, it is intended to assist clini-
evidence emerges that warrants revi-             was published and a systematic re-           cians in decision-making. It is not in-
sion sooner. The guideline is intended           view of the literature on the effective-     tended to replace clinical judgment or to


596    FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS


                                                                                              tainer, because they may be contami-
                                                                                              nated by bacteria in the distal urethra.
                                                                                              Cultures of urine specimens collected
                                                                                              in a bag applied to the perineum have
                                                                                              an unacceptably high false-positive
                                                                                              rate and are valid only when they yield
                                                                                              negative results.6,14–16 With a preva-
                                                                                              lence of UTI of 5% and a high rate of
                                                                                              false-positive results (specificity:
                                                                                              ϳ63%), a “positive” culture result for
FIGURE 1                                                                                      urine collected in a bag would be a
AAP evidence strengths.                                                                       false-positive result 88% of the time.
                                                                                              For febrile boys, with a prevalence of
                                                                                              UTI of 2%, the rate of false-positive re-
establish an exclusive protocol for the           administered, because the antimicro-        sults is 95%; for circumcised boys,
care of all children with this condition.         bial agents commonly prescribed in          with a prevalence of UTI of 0.2%, the
                                                  such situations would almost certainly      rate of false-positive results is 99%.
DIAGNOSIS                                         obscure the diagnosis of UTI.
                                                                                              Therefore, in cases in which antimicro-
Action Statement 1                                SPA has been considered the standard        bial therapy will be initiated, catheter-
If a clinician decides that a febrile             method for obtaining urine that is un-      ization or SPA is required to establish
infant with no apparent source for                contaminated by perineal flora. Vari-        the diagnosis of UTI.
the fever requires antimicrobial                  able success rates for obtaining urine
                                                                                              ● Aggregate quality of evidence: A (diag-
therapy to be administered be-                    have been reported (23%–90%).6–8
                                                                                                nostic studies on relevant populations).
cause of ill appearance or another                When ultrasonographic guidance is
pressing reason, the clinician                    used, success rates improve.9,10 The        ● Benefits: A missed diagnosis of UTI
should ensure that a urine speci-                 technique has limited risks, but tech-        can lead to renal scarring if left un-
men is obtained for both culture                  nical expertise and experience are            treated; overdiagnosis of UTI can
and urinalysis before an antimicro-               required, and many parents and phy-           lead to overtreatment and unneces-
bial agent is administered; the                   sicians perceive the procedure as             sary and expensive imaging. Once an-
specimen needs to be obtained                     unacceptably invasive, compared               timicrobial therapy is initiated, the op-
through catheterization or SPA, be-               with catheterization. However, there          portunity to make a definitive
cause the diagnosis of UTI cannot                 may be no acceptable alternative to           diagnosis is lost; multiple studies of
be established reliably through cul-              SPA for boys with moderate or se-             antimicrobial therapy have shown
ture of urine collected in a bag                  vere phimosis or girls with tight la-         that the urine may be rapidly
(evidence quality: A; strong                      bial adhesions.                               sterilized.
recommendation).                                  Urine obtained through catheteriza-         ● Harms/risks/costs: Catheterization
When evaluating febrile infants, clini-           tion for culture has a sensitivity of 95%     is invasive.
cians make a subjective assessment of             and a specificity of 99%, compared           ● Benefit-harms assessment: Prepon-
the degree of illness or toxicity, in ad-         with that obtained through SPA.7,11,12        derance of benefit over harm.
dition to seeking an explanation for the          The techniques required for catheter-
                                                                                              ● Value judgments: Once antimicro-
fever. This clinical assessment deter-            ization and SPA are well described.13
                                                                                                bial therapy has begun, the opportu-
mines whether antimicrobial therapy               When catheterization or SPA is being
                                                  attempted, the clinician should have a        nity to make a definitive diagnosis is
should be initiated promptly and af-
                                                  sterile container ready to collect a          lost. Therefore, it is important to
fects the diagnostic process regarding
UTI. If the clinician determines that the         urine specimen, because the prepara-          have the most-accurate test for UTI
degree of illness warrants immediate              tion for the procedure may stimulate          performed initially.
antimicrobial therapy, then a urine               the child to void. Whether the urine is     ● Role of patient preferences: There is
specimen suitable for culture should              obtained through catheterization or is        no evidence regarding patient pref-
be obtained through catheterization or            voided, the first few drops should be          erences for bag versus catheterized
SPA before antimicrobial agents are               allowed to fall outside the sterile con-      urine. However, bladder tap has


PEDIATRICS Volume 128, Number 3, September 2011                                                                                      597
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been shown to be more painful than
  urethral catheterization.
● Exclusions: None.
● Intentional vagueness: The basis of
  the determination that antimicro-
  bial therapy is needed urgently is
  not specified, because variability in
  clinical judgment is expected; con-
  siderations for individual patients,
  such as availability of follow-up
  care, may enter into the decision,             FIGURE 2
  and the literature provides only gen-          Probability of UTI Among Febrile Infant Girls28 and Infant Boys30 According to Number of Findings
                                                 Present. aProbability of UTI exceeds 1% even with no risk factors other than being uncircumcised.
  eral guidance.
● Policy level: Strong recommendation.
                                                 be obtained through catheteriza-                   than 1% for 10.4% of academicians and
Action Statement 2
                                                 tion or SPA and cultured; if urinaly-              11.7% for practitioners26; when the
If a clinician assesses a febrile infant         sis of fresh (<1 hour since void)                  threshold was increased to 1% to 3%,
with no apparent source for the fever            urine yields negative leukocyte es-                67.5% of academicians and 45.7% of
as not being so ill as to require imme-          terase and nitrite test results, then              practitioners considered the yield suf-
diate antimicrobial therapy, then the            it is reasonable to monitor the clin-              ficiently high to warrant urine culture.
clinician should assess the likelihood of        ical course without initiating anti-               Therefore, attempting to operational-
UTI (see below for how to assess                 microbial therapy, recognizing that                ize “low likelihood” (ie, below a thresh-
likelihood).                                     negative urinalysis results do not                 old that warrants a urine culture) does
                                                 rule out a UTI with certainty.                     not produce an absolute percentage;
Action Statement 2a                              If the clinician determines that the de-           clinicians will choose a threshold de-
If the clinician determines the febrile          gree of illness does not require imme-             pending on factors such as their confi-
infant to have a low likelihood of UTI           diate antimicrobial therapy, then the              dence that contact will be maintained
(see text), then clinical follow-up              likelihood of UTI should be assessed.              through the illness (so that a specimen
monitoring without testing is suffi-              As noted previously, the overall preva-            can be obtained at a later time) and com-
cient (evidence quality: A; strong               lence of UTI in febrile infants who have           fort with diagnostic uncertainty. Fig 2 in-
recommendation).                                 no source for their fever evident on the           dicates the number of risk factors as-
                                                 basis of history or physical examina-              sociated with threshold probabilities
Action Statement 2b                              tion results is approximately 5%,17,18             of UTI of at least 1% and at least 2%.
If the clinician determines that the             but it is possible to identify groups              In a series of studies, Gorelick, Shaw,
febrile infant is not in a low-risk              with higher-than-average likelihood                and colleagues27–29 derived and vali-
group (see below), then there are 2              and some with lower-than-average                   dated a prediction rule for febrile in-
choices (evidence quality: A; strong             likelihood. The prevalence of UTI                  fant girls on the basis of 5 risk factors,
recommendation). Option 1 is to ob-              among febrile infant girls is more than            namely, white race, age less than 12
tain a urine specimen through cath-              twice that among febrile infant boys               months, temperature of at least 39°C,
eterization or SPA for culture and               (relative risk: 2.27). The rate for uncir-         fever for at least 2 days, and absence
urinalysis. Option 2 is to obtain a              cumcised boys is 4 to 20 times higher              of another source of infection. This
urine specimen through the most                  than that for circumcised boys, whose              prediction rule, with sensitivity of
convenient means and to perform a                rate of UTI is only 0.2% to 0.4%.19–24 The         88% and specificity of 30%, permits
urinalysis. If the urinalysis results            presence of another, clinically obvious            some infant girls to be considered in
suggest a UTI (positive leukocyte                source of infection reduces the likeli-            a low-likelihood group (Fig 2). For ex-
esterase test results or nitrite test            hood of UTI by one-half.25                         ample, of girls with no identifiable
or microscopic analysis results                  In a survey asking, “What yield is re-             source of infection, those who are non-
positive for leukocytes or bacte-                quired to warrant urine culture in fe-             white and more than 12 months of age
ria), then a urine specimen should               brile infants?,” the threshold was less            with a recent onset (Ͻ2 days) of low-


598    FROM THE AMERICAN ACADEMY OF PEDIATRICS
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grade fever (Ͻ39°C) have less than a              TABLE 1 Sensitivity and Specificity of Components of Urinalysis, Alone and in Combination
1% probability of UTI; each additional                      Test                         Sensitivity (Range), %                Specificity (Range), %
risk factor increases the probability. It         Leukocyte esterase test                    83 (67–94)                            78 (64–92)
                                                  Nitrite test                               53 (15–82)                            98 (90–100)
should be noted, however, that some               Leukocyte esterase or                      93 (90–100)                           72 (58–91)
of the factors (eg, duration of fever)               nitrite test positive
may change during the course of the               Microscopy, WBCs                           73 (32–100)                           81 (45–98)
                                                  Microscopy, bacteria                       81 (16–99)                            83 (11–100)
illness, excluding the infant from a              Leukocyte esterase test,                   99.8 (99–100)                         70 (60–92)
low-likelihood designation and                       nitrite test, or
prompting testing as described in                    microscopy positive
action statement 2a.
As demonstrated in Fig 2, the major               definitive urine specimen through                   Action Statement 3
risk factor for febrile infant boys is            catheterization initially.
whether they are circumcised. The prob-                                                              To establish the diagnosis of UTI,
                                                  ● Aggregate quality of evidence: A (diag-          clinicians should require both uri-
ability of UTI can be estimated on the ba-
                                                     nostic studies on relevant populations).        nalysis results that suggest infec-
sis of 4 risk factors, namely, nonblack
race, temperature of at least 39°C, fever         ● Benefits: Accurate diagnosis of UTI               tion (pyuria and/or bacteriuria)
                                                     can prevent the spread of infection             and the presence of at least 50 000
for more than 24 hours, and absence of
                                                     and renal scarring; avoiding overdi-            colony-forming units (CFUs) per mL
another source of infection.4,30
                                                     agnosis of UTI can prevent over-                of a uropathogen cultured from a
If the clinician determines that the in-             treatment and unnecessary and ex-               urine specimen obtained through
fant does not require immediate anti-                pensive imaging.                                catheterization or SPA (evidence
microbial therapy and a urine speci-                                                                 quality: C; recommendation).
                                                  ● Harms/risks/costs: A small propor-
men is desired, then often a urine
                                                     tion of febrile infants, considered at
collection bag affixed to the perineum                                                                Urinalysis
                                                     low likelihood of UTI, will not receive
is used. Many clinicians think that this
                                                     timely identification and treatment              General Considerations
collection technique has a low contam-               of their UTIs.
ination rate under the following cir-                                                                Urinalysis cannot substitute for urine
                                                  ● Benefit-harms assessment: Prepon-                 culture to document the presence of
cumstances: the patient’s perineum is
                                                     derance of benefit over harm.                    UTI but needs to be used in conjunction
properly cleansed and rinsed before
application of the collection bag, the            ● Value judgments: There is a risk of              with culture. Because urine culture re-
                                                     UTI sufficiently low to forestall fur-           sults are not available for at least 24
urine bag is removed promptly after
                                                     ther evaluation.                                hours, there is considerable interest
urine is voided into the bag, and the
                                                  ● Role of patient preferences: The
                                                                                                     in tests that may predict the results of
specimen is refrigerated or processed
                                                     choice of option 1 or option 2 and              the urine culture and enable presump-
immediately. Even if contamination
                                                     the threshold risk of UTI warranting            tive therapy to be initiated at the first
from the perineal skin is minimized,
                                                     obtaining a urine specimen may be               encounter. Urinalysis can be per-
however, there may be significant con-                                                                formed on any specimen, including
tamination from the vagina in girls or               influenced by parents’ preference
                                                     to avoid urethral catheterization (if           one collected from a bag applied to the
the prepuce in uncircumcised boys,                                                                   perineum. However, the specimen
the 2 groups at highest risk of UTI. A               a bag urine sample yields negative
                                                     urinalysis results) versus timely               must be fresh (Ͻ1 hour after voiding
“positive” culture result from a speci-                                                              with maintenance at room tempera-
                                                     evaluation (obtaining a definitive
men collected in a bag cannot be used                                                                ture or Ͻ4 hours after voiding with re-
                                                     specimen through catheterization).
to document a UTI; confirmation re-                                                                   frigeration), to ensure sensitivity and
quires culture of a specimen collected            ● Exclusions: Because it depends on a
                                                                                                     specificity of the urinalysis. The tests
through catheterization or SPA. Be-                  range of patient- and physician-
                                                                                                     that have received the most atten-
cause there may be substantial delay                 specific considerations, the precise
                                                                                                     tion are biochemical analyses of leu-
waiting for the infant to void and a sec-            threshold risk of UTI warranting ob-
                                                                                                     kocyte esterase and nitrite through a
ond specimen, obtained through cath-                 taining a urine specimen is left to
                                                                                                     rapid dipstick method and urine
eterization, may be necessary if the                 the clinician but is below 3%.
                                                                                                     microscopic examination for white
urinalysis suggests the possibility of            ● Intentional vagueness: None.                     blood cells (WBCs) and bacteria
UTI, many clinicians prefer to obtain a           ● Policy level: Strong recommendation.             (Table 1).


PEDIATRICS Volume 128, Number 3, September 2011                                                                                                  599
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Urine dipsticks are appealing, because           64%–92%]) generally is not as good as        during infancy. In a study of infants 2 to
they provide rapid results, do not re-           the sensitivity, which reflects the non-      24 months of age, 0.7% of afebrile girls
quire microscopy, and are eligible for           specificity of pyuria in general. Accord-     had 3 successive urine cultures with
a waiver under the Clinical Laboratory           ingly, positive leukocyte esterase test      105 CFUs per mL of a single uropatho-
Improvement Amendments. They indi-               results should be interpreted with cau-      gen.26 Asymptomatic bacteriuria can
cate the presence of leukocyte es-               tion, because false-positive results are     be easily confused with true UTI in a
terase (as a surrogate marker for                common. With numerous conditions             febrile infant but needs to be distin-
pyuria) and urinary nitrite (which is            other than UTI, including fever result-      guished, because studies suggest that
converted from dietary nitrates in the           ing from other conditions (eg, strepto-      antimicrobial treatment may do more
presence of most Gram-negative enteric           coccal infections or Kawasaki dis-           harm than good.36 The key to distin-
bacteria in the urine). The conversion of        ease), and after vigorous exercise,          guishing true UTI from asymptomatic
dietary nitrates to nitrites by bacteria re-     WBCs may be found in the urine. There-       bacteriuria is the presence of pyuria.
quires approximately 4 hours in the              fore, a finding of pyuria by no means
bladder.31 The performance characteris-                                                       Microscopic Analysis for Bacteriuria
                                                 confirms that an infection of the uri-
tics of both leukocyte esterase and ni-          nary tract is present.                       The presence of bacteria in a fresh,
trite tests vary according to the defini-                                                      Gram-stained specimen of uncentri-
                                                 The absence of pyuria in children with
tion used for positive urine culture                                                          fuged urine correlates with 105 CFUs
                                                 true UTIs is rare, however. It is theoret-
results, the age and symptoms of the                                                          per mL in culture.37 An “enhanced uri-
                                                 ically possible if a febrile child is as-
population being studied, and the                                                             nalysis,” combining the counting
                                                 sessed before the inflammatory re-
method of urine collection.                                                                   chamber assessment of pyuria noted
                                                 sponse has developed, but the
                                                                                              previously with Gram staining of drops
Nitrite Test                                     inflammatory response to a UTI pro-
                                                                                              of uncentrifuged urine, with a thresh-
                                                 duces both fever and pyuria; therefore,
A nitrite test is not a sensitive marker                                                      old of at least 1 Gram-negative rod in
for children, particularly infants, who          children who are being evaluated be-
                                                                                              10 oil immersion fields, has greater sen-
empty their bladders frequently.                 cause of fever should already have
                                                                                              sitivity, specificity, and positive predic-
Therefore, negative nitrite test results         WBCs in their urine. More likely expla-
                                                                                              tive value than does the standard urinal-
have little value in ruling out UTI. More-       nations for significant bacteriuria in
                                                                                              ysis33 and is the preferred method of
over, not all urinary pathogens reduce           culture in the absence of pyuria in-
                                                                                              urinalysis when appropriate equipment
nitrate to nitrite. The test is helpful          clude contaminated specimens, insen-
                                                                                              and personnel are available.
when the result is positive, however,            sitive criteria for pyuria, and asymp-
because it is highly specific (ie, there          tomatic bacteriuria. In most cases,          Automated Urinalysis
are few false-positive results).32               when true UTI has been reported to oc-       Automated methods to perform uri-
                                                 cur in the absence of pyuria, the defi-       nalysis are now being used in many
Leukocyte Esterase Test                          nition of pyuria has been at fault. The      hospitals and laboratories. Image-
The sensitivity of the leukocyte es-             standard method of assessing pyuria          based systems use flow imaging
terase test is 94% when it used in the           has been centrifugation of the urine         analysis technology and software to
context of clinically suspected UTI.             and microscopic analysis, with a             classify particles in uncentrifuged
Overall, the reported sensitivity in var-        threshold of 5 WBCs per high-power           urine specimens rapidly.38 Results
ious studies is lower (83%), because             field (ϳ25 WBCs per ␮L). If a counting        correlate well with manual methods,
the results of leukocyte esterase tests          chamber is used, however, the finding         especially for red blood cells, WBCs,
were related to culture results without          of at least 10 WBCs per ␮L in uncentri-      and squamous epithelial cells. In the
exclusion of individuals with asymp-             fuged urine has been demonstrated to         future, this may be the most common
tomatic bacteriuria. The absence of              be more sensitive33 and performs well        method by which urinalysis is per-
leukocyte esterase in the urine of indi-         in clinical situations in which the stan-    formed in laboratories.
viduals with asymptomatic bacteriuria            dard method does not, such as with
is an advantage of the test, rather than         very young infants.34                        Culture
a limitation, because it distinguishes           An important cause of bacteriuria in         The diagnosis of UTI is made on the ba-
individuals with asymptomatic bacte-             the absence of pyuria is asymptomatic        sis of quantitative urine culture re-
riuria from those with true UTI.                 bacteriuria. Asymptomatic bacteriuria        sults in addition to evidence of pyuria
The specificity of the leukocyte es-              often is associated with school-aged         and/or bacteriuria. Urine specimens
terase test (average: 72% [range:                and older girls,35 but it can be present     should be processed as expediently as


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possible. If the specimen is not pro-             spp are not considered clinically rele-    ● Harms/risks/costs: Stringent diag-
cessed promptly, then it should be re-            vant urine isolates for otherwise             nostic criteria may miss a small
frigerated to prevent the growth of or-           healthy, 2- to 24-month-old children.)        number of UTIs.
ganisms that can occur in urine at                Reducing the threshold from 100 000        ● Benefit-harms assessment: Prepon-
room temperature; for the same rea-               CFUs per mL to 50 000 CFUs per mL             derance of benefit over harm.
son, specimens that require transpor-             would seem to increase the sensitivity
                                                                                             ● Value judgments: Treatment of
tation to another site for processing             of culture at the expense of decreased
                                                                                                asymptomatic bacteriuria may be
should be transported on ice. A prop-             specificity; however, because the pro-
                                                                                                harmful.
erly collected urine specimen should              posed criteria for UTI now include evi-
                                                  dence of pyuria in addition to positive    ● Role of patient preferences: We as-
be inoculated on culture medium that
                                                  culture results, infants with “positive”      sume that parents prefer no action
will allow identification of urinary tract
                                                  culture results alone will be recog-          in the absence of a UTI (avoiding
pathogens.
                                                  nized as having asymptomatic bacteri-         false-positive results) over a very
Urine culture results are considered                                                            small chance of missing a UTI.
                                                  uria rather than a true UTI. Some labo-
positive or negative on the basis of the
                                                  ratories report growth only in the         ● Exclusions: None.
number of CFUs that grow on the cul-
ture medium.36 Definition of significant
                                                  following categories: 0 to 1000, 1000 to   ● Intentional vagueness: None.
                                                  10 000, 10 000 to 100 000, and more        ● Policy level: Recommendation.
colony counts with regard to the
                                                  than 100 000 CFUs per mL. In such
method of collection considers that
                                                  cases, results in the 10 000 to 100 000    MANAGEMENT
the distal urethra and periurethral
                                                  CFUs per mL range need to be evalu-
area are commonly colonized by the                                                           Action Statement 4
                                                  ated in context, such as whether the
same bacteria that may cause UTI;
                                                  urinalysis findings support the diagno-     Action Statement 4a
therefore, a low colony count may be
                                                  sis of UTI and whether the organism is
present in a specimen obtained                                                               When initiating treatment, the clini-
                                                  a recognized uropathogen.
through voiding or catheterization                                                           cian should base the choice of
when bacteria are not present in blad-            Alternative culture methods, such as       route of administration on practi-
der urine. Definitions of positive and             dipslides, may have a place in the of-     cal considerations. Initiating treat-
negative culture results are opera-               fice setting; sensitivity is reported to    ment orally or parenterally is
tional and not absolute. The time the             be in the range of 87% to 100%, and        equally efficacious. The clinician
urine resides in the bladder (bladder             specificity is reported to be 92% to        should base the choice of agent on
incubation time) is an important deter-           98%, but dipslides cannot specify the      local antimicrobial sensitivity pat-
minant of the magnitude of the colony             organism or antimicrobial sensitivi-       terns (if available) and should ad-
                                                  ties.41 Practices that use dipslides       just the choice according to sensi-
count. The concept that more than
                                                  should do so in collaboration with a       tivity testing of the isolated
100 000 CFUs per mL indicates a UTI
                                                  certified laboratory for identification      uropathogen (evidence quality: A;
was based on morning collections of
                                                  and sensitivity testing or, in the ab-     strong recommendation).
urine from adult women, with compar-
                                                  sence of such results, may need to per-
ison of specimens from women with-
                                                  form “test of cure” cultures after 24      Action Statement 4b
out symptoms and women considered
                                                  hours of treatment.                        The clinician should choose 7 to 14
clinically to have pyelonephritis; the
transition range, in which the propor-            ● Aggregate quality of evidence: C (ob-    days as the duration of antimicrobial
tion of women with pyelonephritis ex-               servational studies).                    therapy (evidence quality: B;
ceeded the proportion of women with-              ● Benefits: Accurate diagnosis of UTI       recommendation).
out symptoms, was 10 000 to 100 000                 can prevent the spread of infection      The goals of treatment of acute UTI are
CFUs per mL.39 In most instances, an                and renal scarring; avoiding overdi-     to eliminate the acute infection, to pre-
appropriate threshold to consider                   agnosis of UTI can prevent over-         vent complications, and to reduce the
bacteriuria “significant” in infants and             treatment and unnecessary and ex-        likelihood of renal damage. Most chil-
children is the presence of at least                pensive imaging. These criteria          dren can be treated orally.42–44 Patients
50 000 CFUs per mL of a single urinary              reduce the likelihood of overdiagno-     whom clinicians judge to be “toxic” or
pathogen.40 (Organisms such as                      sis of UTI in infants with asymptom-     who are unable to retain oral intake
Lactobacillus spp, coagulase-negative               atic bacteriuria or contaminated         (including medications) should re-
staphylococci, and Corynebacterium                  specimens.                               ceive an antimicrobial agent parenter-


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TABLE 2 Some Empiric Antimicrobial Agents           TABLE 3 Some Empiric Antimicrobial Agents for Oral Treatment of UTI
           for Parenteral Treatment of UTI                 Antimicrobial Agent                                      Dosage
Antimicrobial                     Dosage            Amoxicillin-clavulanate                20–40 mg/kg per d in 3 doses
    Agent                                           Sulfonamide
Ceftriaxone                75 mg/kg, every 24 h       Trimethoprim-sulfamethoxazole        6–12 mg/kg trimethoprim and 30-60 mg/kg sulfamethoxazole
Cefotaxime                 150 mg/kg per d,                                                  per d in 2 doses
                              divided every 6–8 h     Sulfisoxazole                         120–150 mg/kg per d in 4 doses
Ceftazidime                100–150 mg/kg per d,     Cephalosporin
                              divided every 8 h       Cefixime                              8 mg/kg per d in 1 dose
 Gentamicin                7.5 mg/kg per d,           Cefpodoxime                          10 mg/kg per d in 2 doses
                              divided every 8 h       Cefprozil                            30 mg/kg per d in 2 doses
Tobramycin                 5 mg/kg per d,             Cefuroxime axetil                    20–30 mg/kg per d in 2 doses
                              divided every 8 h       Cephalexin                           50–100 mg/kg per d in 4 doses
 Piperacillin              300 mg/kg per d,
                              divided every 6–8 h


                                                    the total course of therapy should be 7              distinguishes the benefit of treating
ally (Table 2) until they exhibit clinical          to 14 days. The committee attempted to               7 vs 10 vs 14 days, and the range is
improvement, generally within 24 to 48              identify a single, preferred, evidence-              allowable.
hours, and are able to retain orally ad-            based duration, rather than a range, but          ● Policy level: Strong recommendation/
ministered fluids and medications. In a              data comparing 7, 10, and 14 days di-
study of 309 febrile infants with UTIs,                                                                  recommendation.
                                                    rectly were not found. There is evidence
only 3 (1%) were deemed too ill to be               that 1- to 3-day courses for febrile UTIs         Action Statement 5
assigned randomly to either paren-                  are inferior to courses in the recom-
teral or oral treatment.42 Parenteral                                                                 Febrile infants with UTIs should
                                                    mended range; therefore, the minimal
administration of an antimicrobial                                                                    undergo renal and bladder ultra-
                                                    duration selected should be 7 days.
agent also should be considered when                                                                  sonography (RBUS) (evidence
                                                    ● Aggregate quality of evidence: A/B              quality: C; recommendation).
compliance with obtaining an antimi-
crobial agent and/or administering it                  (RCTs).
                                                                                                      The purpose of RBUS is to detect ana-
orally is uncertain. The usual choices              ● Benefits: Adequate treatment of UTI              tomic abnormalities that require fur-
for oral treatment of UTIs include                     can prevent the spread of infection            ther evaluation, such as additional im-
a cephalosporin, amoxicillin plus                      and renal scarring. Outcomes of                aging or urologic consultation. RBUS
clavulanic acid, or trimethoprim-                      short courses (1–3 d) are inferior to          also provides an evaluation of the re-
sulfamethoxazole (Table 3). It is essen-               those of 7- to 14-d courses.                   nal parenchyma and an assessment of
tial to know local patterns of suscepti-            ● Harms/risks/costs: There are mini-              renal size that can be used to monitor
bility of coliforms to antimicrobial                   mal harm and minor cost effects of             renal growth. The yield of actionable
agents, particularly trimethoprim-                     antimicrobial choice and duration              findings is relatively low.45,46 Wide-
sulfamethoxazole and cephalexin, be-                   of therapy.                                    spread application of prenatal ultra-
cause there is substantial geographic               ● Benefit-harms assessment: Prepon-                sonography clearly has reduced the
variability that needs to be taken into                derance of benefit over harm.                   prevalence of previously unsuspected
account during selection of an antimi-                                                                obstructive uropathy in infants, but the
                                                    ● Value judgments: Adjusting antimi-
crobial agent before sensitivity results                                                              consequences of prenatal screening
                                                       crobial choice on the basis of avail-
are available. Agents that are excreted                                                               with respect to the risk of renal abnor-
                                                       able data and treating according to
in the urine but do not achieve thera-                                                                malities in infants with UTIs have not
                                                       best evidence will minimize cost and
peutic concentrations in the blood-                                                                   yet been well defined. There is consid-
                                                       consequences of failed or unneces-
stream, such as nitrofurantoin, should                                                                erable variability in the timing and
                                                       sary treatment.
not be used to treat febrile infants with                                                             quality of prenatal ultrasonograms,
UTIs, because parenchymal and serum                 ● Role of patient preferences: It is as-
                                                                                                      and the report of “normal” ultrasono-
antimicrobial concentrations may be                    sumed that parents prefer the
                                                                                                      graphic results cannot necessarily be
insufficient to treat pyelonephritis or                 most-effective treatment and the
                                                                                                      relied on to dismiss completely the
urosepsis.                                             least amount of medication that en-
                                                                                                      possibility of a structural abnormality
                                                       sures effective treatment.
Whether the initial route of administra-                                                              unless the study was a detailed ana-
tion of the antimicrobial agent is oral             ● Exclusions: None.                               tomic survey (with measurements),
or parenteral (then changed to oral),               ● Intentional vagueness: No evidence              was performed during the third tri-


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mester, and was performed and inter-              children with reduced renal function.      Action Statement 6
preted by qualified individuals.47                 The radiation dose from dimercapto-
                                                                                             Action Statement 6a
The timing of RBUS depends on the                 succinic acid is additive with that of
                                                                                             VCUG should not be performed
clinical situation. RBUS is recom-                VCUG when both studies are per-
                                                                                             routinely after the first febrile
mended during the first 2 days of treat-           formed.50 The radiation dose from
                                                                                             UTI; VCUG is indicated if RBUS re-
ment to identify serious complications,           VCUG depends on the equipment that
                                                                                             veals hydronephrosis, scarring,
such as renal or perirenal abscesses              is used (conventional versus pulsed
                                                                                             or other findings that would sug-
or pyonephrosis associated with ob-               digital fluoroscopy) and is related di-
                                                                                             gest either high-grade VUR or ob-
structive uropathy when the clinical ill-         rectly to the total fluoroscopy time.       structive uropathy, as well as in
ness is unusually severe or substantial           Moreover, the total exposure for the       other atypical or complex clinical
clinical improvement is not occurring.            child will be increased when both          circumstances (evidence quality
For febrile infants with UTIs who dem-            acute and follow-up studies are ob-        B; recommendation).
onstrate substantial clinical improve-            tained. The lack of exposure to radi-
ment, however, imaging does not need              ation is a major advantage of RBUS,        Action Statement 6b
to occur early during the acute infec-            even with recognition of the limita-       Further evaluation should be con-
tion and can even be misleading; ani-             tions of this modality that were de-       ducted if there is a recurrence of fe-
mal studies demonstrate that Esche-               scribed previously.                        brile UTI (evidence quality: X;
richia coli endotoxin can produce                                                            recommendation).
                                                  ● Aggregate quality of evidence: C (ob-
dilation during acute infection, which
                                                    servational studies).                    For the past 4 decades, the strategy to
could be confused with hydronephro-
                                                  ● Benefits: RBUS in this population
                                                                                             protect the kidneys from further dam-
sis, pyonephrosis, or obstruction.48
                                                                                             age after an initial UTI has been to de-
Changes in the size and shape of the                will yield abnormal results in ϳ15%
                                                                                             tect childhood genitourinary abnor-
kidneys and the echogenicity of renal               of cases, and 1% to 2% will have ab-
                                                                                             malities in which recurrent UTI could
parenchyma attributable to edema                    normalities that would lead to ac-
                                                                                             increase renal damage. The most com-
also are common during acute infec-                 tion (eg, additional evaluation, re-
                                                                                             mon of these is VUR, and VCUG is used
tion. The presence of these abnormal-               ferral, or surgery).
                                                                                             to detect this. Management included
ities makes it inappropriate to con-              ● Harms/risks/costs:    Between 2%         continuous antimicrobial administra-
sider RBUS performed early during                   and 3% will be false-positive results,   tion as prophylaxis and surgical inter-
acute infection to be a true baseline               leading to unnecessary and invasive      vention if VUR was persistent or recur-
study for later comparisons in the as-              evaluations.                             rences of infection were not prevented
sessment of renal growth.                                                                    with an antimicrobial prophylaxis reg-
                                                  ● Benefit-harms assessment: Prepon-
Nuclear scanning with technetium-                   derance of benefit over harm.             imen; some have advocated surgical
labeled dimercaptosuccinic acid has                                                          intervention to correct high-grade re-
                                                  ● Value judgments: The seriousness
greater sensitivity for detection of                                                         flux even when infection has not re-
acute pyelonephritis and later scar-                of the potentially correctable abnor-
                                                                                             curred. However, it is clear that there
ring than does either RBUS or voiding               malities in 1% to 2%, coupled with       are a significant number of infants
cystourethrography (VCUG). The scan-                the absence of physical harm, was        who develop pyelonephritis in whom
ning is useful in research, because it              judged sufficiently important to tip      VUR cannot be demonstrated, and the
ensures that all subjects in a study                the scales in favor of testing.          effectiveness of antimicrobial prophy-
have pyelonephritis to start with and it          ● Role of patient preferences: Be-         laxis for patients who have VUR has
permits assessment of later renal                   cause ultrasonography is noninva-        been challenged in the past decade.
scarring as an outcome measure. The                 sive and poses minimal risk, we as-      Several studies have suggested that
findings on nuclear scans rarely affect              sume that parents will prefer RBUS       prophylaxis does not confer the de-
acute clinical management, however,                 over taking even a small risk of         sired benefit of preventing recurrent
and are not recommended as part of                  missing a serious and correctable        febrile UTI.51–55 If prophylaxis is, in fact,
routine evaluation of infants with their            condition.                               not beneficial and VUR is not required
first febrile UTI. The radiation dose to                                                      for development of pyelonephritis,
                                                  ● Exclusions: None.
the patient during dimercaptosuccinic                                                        then the rationale for performing
acid scanning is generally low (ϳ1                ● Intentional vagueness: None.             VCUG routinely after an initial febrile
mSv),49 although it may be increased in           ● Policy level: Recommendation.            UTI must be questioned.


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RCTs of the effectiveness of prophy-             TABLE 4 Recurrences of Febrile UTI/Pyelonephritis in Infants 2 to 24 Months of Age With and
                                                          Without Antimicrobial Prophylaxis, According to Grade of VUR
laxis performed to date generally in-
                                                 Reflux                    Prophylaxis                            No Prophylaxis                 P
cluded children more than 24 months
                                                 Grade
of age, and some did not provide com-                               No. of              Total N            No. of                 Total N
                                                                 Recurrences                            Recurrences
plete data according to grade of VUR.
                                                 None                 7                  210                11                     163          .15
These 2 factors have compromised                 I                    2                   37                 2                      35         1.00
meta-analyses. To ensure direct com-             II                  11                  133                10                     124          .95
parisons, the committee contacted the            III                 31                  140                40                     145          .29
                                                 IV                  16                   55                21                      49          .14
6 researchers who had conducted the
most recent RCTs and requested raw
data from their studies.51–56 All com-           the initial UTI, those who have the                ● Benefits: This avoids, for the vast
plied, which permitted the creation of           greatest likelihood of having high-                   majority of febrile infants with UTIs,
a data set with data for 1091 infants 2          grade VUR. Unfortunately, there are no                radiation exposure (of particular
to 24 months of age according to grade           clinical or laboratory indicators that                concern near the ovaries in girls),
of VUR. A ␹2 analysis (2-tailed) and a           have been demonstrated to identify in-                expense, and discomfort.
formal meta-analysis did not detect a            fants with high-grade VUR. Indications             ● Harms/risks/costs: Detection of a
statistically significant benefit of pro-          for VCUG have been proposed on the                    small number of cases of high-
phylaxis in preventing recurrence of             basis of consensus in the absence of                  grade reflux and correctable abnor-
febrile UTI/pyelonephritis in infants            data57; the predictive value of any of the
                                                                                                       malities is delayed.
without reflux or those with grades I, II,        indications for VCUG proposed in this
                                                 manner is not known.                               ● Benefit-harms assessment: Prepon-
III, or IV VUR (Table 4 and Fig 3). Only 5                                                             derance of benefit over harm.
infants with grade V VUR were in-                The level of evidence supporting rou-
                                                 tine imaging with VCUG was deemed                  ● Value judgments: The risks associ-
cluded in the RCTs; therefore, data for
                                                 insufficient at the time of the 1999                   ated with radiation (plus the ex-
those infants are not included in Table
                                                 practice parameter to receive a rec-                  pense and discomfort of the proce-
4 or Fig 3.
                                                 ommendation, but the consensus of                     dure) for the vast majority of infants
The proportion of infants with high-                                                                   outweigh the risk of delaying the de-
                                                 the subcommittee was to “strongly en-
grade VUR among all infants with fe-                                                                   tection of the few with correctable
                                                 courage” imaging studies. The position
brile UTIs is small. Data adapted from                                                                 abnormalities until their second UTI.
                                                 of the current subcommittee reflects
current studies (Table 5) indicate that,
                                                 the new evidence demonstrating anti-               ● Role of patient preferences: The
of a hypothetical cohort of 100 infants
                                                 microbial prophylaxis not to be effec-                judgment of parents may come into
with febrile UTIs, only 1 has grade V
                                                 tive as presumed previously. More-                    play, because VCUG is an uncomfort-
VUR; 99 do not. With a practice of wait-
                                                 over, prompt diagnosis and effective                  able procedure involving radiation
ing for a second UTI to perform VCUG,
                                                 treatment of a febrile UTI recurrence                 exposure. In some cases, parents
only 10 of the 100 would need to un-             may be of greater importance regard-
dergo the procedure and the 1 with                                                                     may prefer to subject their children
                                                 less of whether VUR is present or the                 to the procedure even when the
grade V VUR would be identified. (It              child is receiving antimicrobial pro-
also is possible that the 1 infant with                                                                chance of benefit is both small and
                                                 phylaxis. A national study (the Ran-                  uncertain. Antimicrobial prophy-
grade V VUR might have been identified            domized Intervention for Children With
after the first UTI on the basis of abnor-                                                              laxis seems to be ineffective in pre-
                                                 Vesicoureteral Reflux study) is cur-                   venting recurrence of febrile UTI/py-
mal RBUS results that prompted VCUG              rently in progress to identify the ef-
to be performed.) Data to quantify ad-                                                                 elonephritis for the vast majority of
                                                 fects of a prophylactic antimicrobial
ditional potential harm to an infant                                                                   infants. Some parents may want to
                                                 regimen for children 2 months to 6
who is not revealed to have high-grade                                                                 avoid VCUG even after the second
                                                 years of age who have experienced a
VUR until a second UTI are not precise                                                                 UTI. Because the benefit of identify-
                                                 UTI, and it is anticipated to provide ad-
but suggest that the increment is in-                                                                  ing high-grade reflux is still in some
                                                 ditional important data58 (see Areas
sufficient to justify routinely subject-                                                                doubt, these preferences should be
                                                 for Research).
ing all infants with an initial febrile UTI                                                            considered. It is the judgment of the
to VCUG (Fig 4). To minimize any harm            Action Statement 6a                                   committee that VCUG is indicated af-
incurred by that infant, attempts have           ● Aggregate quality of evidence: B                    ter the second UTI.
been made to identify, at the time of               (RCTs).                                         ● Exclusions: None.


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                                                                                                            TABLE 5 Rates of VUR According to Grade in
                                                                                                                      Hypothetical Cohort of Infants After
                                                                                                                      First UTI and After Recurrence
                                                                                                                                               Rate, %
                                                                                                                                 After First           After
                                                                                                                                     UTI            Recurrence
                                                                                                                                 (N ϭ 100)           (N ϭ 10)
                                                                                                            No VUR                   65                  26
                                                                                                            Grades I–III VUR         29                  56
                                                                                                            Grade IV VUR              5                  12
                                                                                                            Grade V VUR               1                   6




                                                                                                            FIGURE 4
                                                                                                            Relationship between renal scarring and num-
                                                                                                            ber of bouts of pyelonephritis. Adapted from
                                                                                                            Jodal.59


                                                                                                            ● Intentional vagueness: None.
                                                                                                            ● Policy level: Recommendation.

                                                                                                            Action Statement 6b
                                                                                                            ● Aggregate quality of evidence: X (ex-
                                                                                                               ceptional situation).
                                                                                                            ● Benefits: VCUG after a second UTI
                                                                                                               should identify infants with very
                                                                                                               high-grade reflux.
                                                                                                            ● Harms/risks/costs: VCUG is an un-
                                                                                                               comfortable, costly procedure that
                                                                                                               involves radiation, including to the
                                                                                                               ovaries of girls.
                                                                                                            ● Benefit-harms assessment: Prepon-
FIGURE 3                                                                                                       derance of benefit over harm.
A, Recurrences of febrile UTI/pyelonephritis in 373 infants 2 to 24 months of age without VUR, with and
without antimicrobial prophylaxis (based on 3 studies; data provided by Drs Craig, Garin, and Mon-          ● Value judgments: The committee
tini). B, Recurrences of febrile UTI/pyelonephritis in 72 infants 2 to 24 months of age with grade I VUR,      judged that patients with high-
with and without antimicrobial prophylaxis (based on 4 studies; data provided by Drs Craig, Garin,
Montini, and Roussey-Kesler). C, Recurrences of febrile UTI/pyelonephritis in 257 infants 2 to 24
                                                                                                               grade reflux and other abnormali-
months of age with grade II VUR, with and without antimicrobial prophylaxis (based on 5 studies; data          ties may benefit from interventions
provided by Drs Craig, Garin, Montini, Pennesi, and Roussey-Kesler). D, Recurrences of febrile UTI/            to prevent further scarring. Further
pyelonephritis in 285 infants 2 to 24 months of age with grade III VUR, with and without antimicrobial
prophylaxis (based on 6 studies; data provided by Drs Brandström, Craig, Garin, Montini, Pennesi, and          studies of treatment for grade V
Roussey-Kesler). E, Recurrences of febrile UTI/pyelonephritis in 104 infants 2 to 24 months of age with        VUR are not underway and are un-
grade IV VUR, with and without antimicrobial prophylaxis (based on 3 studies; data provided by Drs             likely in the near future, because the
Brandström, Craig, and Pennesi). M-H indicates Mantel-Haenszel; CI, confidence interval.
                                                                                                               condition is uncommon and ran-
                                                                                                               domization of treatment in this
                                                                                                               group generally has been consid-
                                                                                                               ered unethical.


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● Role of patient preferences: As men-          ● Aggregate quality of evidence: C (ob-    first UTI is not recommended; VCUG is
  tioned previously, the judgment of              servational studies).                    indicated if RBUS reveals hydrone-
  parents may come into play, be-               ● Benefits: Studies suggest that early      phrosis, scarring, or other findings
  cause VCUG is an uncomfortable                  treatment of UTI reduces the risk of     that would suggest either high-grade
  procedure involving radiation expo-             renal scarring.                          VUR or obstructive uropathy, as well as
  sure. In some cases, parents may                                                         in other atypical or complex clinical
                                                ● Harms/risks/costs: There may be
  prefer to subject their children to                                                      circumstances. VCUG also should be
                                                  additional costs and inconvenience
  the procedure even when the                                                              performed if there is a recurrence of
                                                  to parents with more-frequent visits
  chance of benefit is both small and                                                       febrile UTI.
                                                  to the clinician for evaluation of
  uncertain. The benefits of treatment
                                                  fever.
  of VUR remain unproven, but the                                                          AREAS FOR RESEARCH
  point estimates suggest a small po-           ● Benefit-harms assessment: Prepon-
                                                  derance of benefit over harm.             One of the major values of a compre-
  tential benefit. Similarly, parents                                                       hensive literature review is the identi-
  may want to avoid VCUG even after             ● Value judgments: None.
                                                                                           fication of areas in which evidence is
  the second UTI. Because the benefit            ● Role of patient preferences: Parents     lacking. The following 8 areas are pre-
  of identifying high-grade reflux is              will ultimately make the judgment to     sented in an order that parallels the
  still in some doubt, these prefer-              seek medical care.                       previous discussion.
  ences should be considered. It is the         ● Exclusions: None.                        1. The relationship between UTIs in in-
  judgment of the committee that
                                                ● Intentional vagueness: None.                fants and young children and re-
  VCUG is indicated after the second
                                                ● Policy level: Recommendation.               duced renal function in adults has
  UTI.
                                                                                              been established but is not
● Exclusions: None.
                                                CONCLUSIONS                                   well characterized in quantitative
● Intentional vagueness: Further eval-                                                        terms. The ideal prospective cohort
                                                The committee formulated 7 key action
  uation will likely start with VCUG but                                                      study from birth to 40 to 50 years of
                                                statements for the diagnosis and
  may entail additional studies de-                                                           age has not been conducted and is
                                                treatment of infants and young chil-
  pending on the findings. The details                                                         unlikely to be conducted. There-
                                                dren 2 to 24 months of age with UTI and
  of further evaluation are beyond the                                                        fore, estimates of undesirable
                                                unexplained fever. Strategies for diag-
  scope of this guideline.                                                                    outcomes in adulthood, such as
                                                nosis and treatment depend on
● Policy level: Recommendation.                 whether the clinician determines that         hypertension and end-stage renal
                                                antimicrobial therapy is warranted im-        disease, are based on the mathe-
Action Statement 7                                                                            matical product of probabilities
                                                mediately or can be delayed safely un-
After confirmation of UTI, the cli-              til urine culture and urinalysis results      at several steps, each of which is
nician should instruct parents or               are available. Diagnosis is based on          subject to bias and error. Other
guardians to seek prompt medical                the presence of pyuria and at least           attempts at decision analysis and
evaluation (ideally within 48                   50 000 CFUs per mL of a single uro-           thoughtful literature review have
hours) for future febrile ill-                  pathogen in an appropriately collected        recognized the same limitations.
nesses, to ensure that recurrent                specimen of urine; urinalysis alone           Until recently, imaging tools avail-
infections can be detected and                  does not provide a definitive diagnosis.       able for assessment of the effects
treated promptly (evidence qual-                After 7 to 14 days of antimicrobial           of UTIs have been insensitive. With
ity: C; recommendation).                        treatment, close clinical follow-up           the imaging techniques now avail-
Early treatment limits renal damage             monitoring should be maintained, with         able, it may be possible to identify
better than late treatment,1,2 and the          evaluation of the urine during subse-         the relationship of scarring to re-
risk of renal scarring increases as the         quent febrile episodes to permit              nal impairment and hypertension.
number of recurrences increase (Fig             prompt diagnosis and treatment of re-      2. The development of techniques that
4).59 For these reasons, all infants who        current infections. Ultrasonography of        would permit an alternative to inva-
have sustained a febrile UTI should             the kidneys and bladder should be per-        sive sampling and culture would be
have a urine specimen obtained at the           formed to detect anatomic abnormali-          valuable for general use. Special at-
onset of subsequent febrile illnesses,          ties that require further evaluation          tention should be given to infant
so that a UTI can be diagnosed and              (eg, additional imaging or urologic           girls and uncircumcised boys, be-
treated promptly.                               consultation). Routine VCUG after the         cause urethral catheterization may


606   FROM THE AMERICAN ACADEMY OF PEDIATRICS
                               Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
FROM THE AMERICAN ACADEMY OF PEDIATRICS


   be difficult and can produce con-                  microbial resistance. To overcome                    the infants will have recurrent UTIs;
   taminated specimens and SPA now                   these issues, evidence of effective-                 some will be identified as having VUR
   is not commonly performed. Incu-                  ness with a well-tolerated, safe                     or other abnormalities. Further re-
   bation time, which is inherent in the             product would be required, and                       search addressing the optimal
   culture process, results in delayed               parents would need sufficient edu-                    course of management in specific sit-
   treatment or presumptive treat-                   cation to understand the value and                   uations would be valuable.
   ment on the basis of tests that lack              importance of adherence. A urinary                8. The optimal duration of antimicro-
   the desired sensitivity and specific-              antiseptic, rather than an antimi-                   bial treatment has not been deter-
   ity to replace culture.                           crobial agent, would be particularly                 mined. RCTs of head-to-head com-
3. The role of VUR (and therefore of                 desirable, because it could be taken                 parisons of various duration would
   VCUG) is incompletely understood.                 indefinitely without concern that                     be valuable, enabling clinicians to
   It is recognized that pyelonephritis              bacteria would develop resistance.                   limit antimicrobial exposure to
   (defined through cortical scintigra-               Another possible strategy might be                   what is needed to eradicate the of-
   phy) can occur in the absence of                  the use of probiotics.                               fending uropathogen.
   VUR (defined through VCUG) and                  5. Better understanding of the ge-
   that progressive renal scarring                   nome (human and bacterial) may                    LEAD AUTHOR
                                                     provide insight into risk factors                 Kenneth B. Roberts, MD
   (defined through cortical scintigra-
   phy) can occur in the absence of                  (VUR and others) that lead to in-                 SUBCOMMITTEE ON URINARY TRACT
   demonstrated VUR.52,53 The pre-                   creased scarring. Blood specimens                 INFECTION, 2009 –2011
   sumption that antimicrobial pro-                  will be retained from children en-                Kenneth B. Roberts, MD, Chair
                                                                                                       Stephen M. Downs, MD, MS
   phylaxis is of benefit for individuals             rolled in the Randomized Interven-
                                                                                                       S. Maria E. Finnell, MD, MS
   with VUR to prevent recurrences of                tion for Children With Vesi-                      Stanley Hellerstein, MD
   UTI or the development of renal scars             coureteral Reflux study, for future                Linda D. Shortliffe, MD
                                                     examination of genetic determinants               Ellen R. Wald, MD
   is not supported by the aggregate of                                                                J. Michael Zerin, MD
   data from recent studies and cur-                 of VUR, recurrent UTI, and renal scar-
   rently is the subject of the Random-              ring.58 VUR is recognized to “run in              OVERSIGHT BY THE STEERING
   ized Intervention for Children With               families,”60,61 and multiple investiga-           COMMITTEE ON QUALITY
                                                     tors are currently engaged in re-                 IMPROVEMENT AND MANAGEMENT,
   Vesicoureteral Reflux study.58
                                                     search to identify a genetic basis for            2009 –2011
4. Although the effectiveness of anti-
   microbial prophylaxis for the pre-                VUR. Studies may also be able to dis-             STAFF
                                                     tinguish the contribution of congeni-             Caryn Davidson, MA
   vention of UTI has not been demon-
                                                     tal dysplasia from acquired scarring
   strated, the concept has biological                                                                 ACKNOWLEDGMENTS
                                                     attributable to UTI.
   plausibility. Virtually all antimicro-                                                              The committee gratefully acknowl-
   bial agents used to treat or to pre-           6. One of the factors used to assess                 edges the generosity of the research-
   vent infections of the urinary tract              the likelihood of UTI in febrile in-              ers who graciously shared their data
   are excreted in the urine in high                 fants is race. Data regarding rates               to permit the data set with data for
   concentrations. Barriers to the ef-               among Hispanic individuals are lim-               1091 infants aged 2 to 24 months ac-
   fectiveness of antimicrobial pro-                 ited and would be useful for predic-              cording to grade of VUR to be com-
   phylaxis are adherence to a daily                 tion rules.                                       piled, that is, Drs Per Brandström,
   regimen, adverse effects associ-               7. This guideline is limited to the initial          Jonathan Craig, Eduardo Garin, Gio-
   ated with the various agents, and                 management of the first UTI in febrile             vanni Montini, Marco Pennesi, and
   the potential for emergence of anti-              infants 2 to 24 months of age. Some of            Gwenaelle Roussey-Kesler.
REFERENCES
 1. Winter AL, Hardy BE, Alton DJ, Arbus GS,       3. American Academy of Pediatrics, Commit-           4. Finnell SM, Carroll AE, Downs SM, et al. Technical
    Churchill BM. Acquired renal scars in chil-       tee on Quality Improvement, Subcommittee             report: diagnosis and management of an initial
    dren. J Urol. 1983;129(6):1190 –1194              on Urinary Tract Infection. Practice                 urinary tract infection in febrile infants and
 2. Smellie JM, Poulton A, Prescod NP. Retro-         parameter: the diagnosis, treatment, and             young children. Pediatrics. 2011;128(3):e749
    spective study of children with renal scar-       evaluation of the initial urinary tract infec-    5. American Academy of Pediatrics, Steering
    ring associated with reflux and urinary in-        tion in febrile infants and young children.          Committee on Quality Improvement and
    fection. BMJ. 1994;308(6938):1193–1196            Pediatrics. 1999;103(4):843– 852                     Management. Classifying recommenda-


PEDIATRICS Volume 128, Number 3, September 2011                                                                                                         607
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Itu 2011 aap
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Itu 2011 aap

  • 1. Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months SUBCOMMITTEE ON URINARY TRACT INFECTION and STEERING COMMITTEE ON QUALITY IMPROVEMENT AND MANAGEMENT Pediatrics; originally published online August 28, 2011; DOI: 10.1542/peds.2011-1330 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2011/08/24/peds.2011-1330 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 2. FROM THE AMERICAN ACADEMY OF PEDIATRICS CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months SUBCOMMITTEE ON URINARY TRACT INFECTION, STEERING COMMITTEE ON QUALITY IMPROVEMENT AND MANAGEMENT abstract KEY WORDS urinary tract infection, infants, children, vesicoureteral reflux, OBJECTIVE: To revise the American Academy of Pediatrics practice voiding cystourethrography parameter regarding the diagnosis and management of initial urinary ABBREVIATIONS tract infections (UTIs) in febrile infants and young children. SPA—suprapubic aspiration METHODS: Analysis of the medical literature published since the last AAP—American Academy of Pediatrics UTI—urinary tract infection version of the guideline was supplemented by analysis of data provided RCT—randomized controlled trial by authors of recent publications. The strength of evidence supporting CFU—colony-forming unit each recommendation and the strength of the recommendation were VUR—vesicoureteral reflux WBC—white blood cell assessed and graded. RBUS—renal and bladder ultrasonography RESULTS: Diagnosis is made on the basis of the presence of both VCUG—voiding cystourethrography pyuria and at least 50 000 colonies per mL of a single uropathogenic This document is copyrighted and is property of the American organism in an appropriately collected specimen of urine. After 7 to 14 Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American days of antimicrobial treatment, close clinical follow-up monitoring Academy of Pediatrics. Any conflicts have been resolved through should be maintained to permit prompt diagnosis and treatment of a process approved by the Board of Directors. The American recurrent infections. Ultrasonography of the kidneys and bladder Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of should be performed to detect anatomic abnormalities. Data from the this publication. most recent 6 studies do not support the use of antimicrobial prophy- The recommendations in this report do not indicate an exclusive laxis to prevent febrile recurrent UTI in infants without vesicoureteral course of treatment or serve as a standard of medical care. reflux (VUR) or with grade I to IV VUR. Therefore, a voiding cystoure- Variations, taking into account individual circumstances, may be thrography (VCUG) is not recommended routinely after the first UTI; appropriate. VCUG is indicated if renal and bladder ultrasonography reveals hydro- All clinical practice guidelines from the American Academy of Pediatrics automatically expire 5 years after publication unless nephrosis, scarring, or other findings that would suggest either high- reaffirmed, revised, or retired at or before that time. grade VUR or obstructive uropathy and in other atypical or complex clinical circumstances. VCUG should also be performed if there is a recurrence of a febrile UTI. The recommendations in this guideline do not indicate an exclusive course of treatment or serve as a standard of care; variations may be appropriate. Recommendations about antimi- crobial prophylaxis and implications for performance of VCUG are based on currently available evidence. As with all American Academy of Pediatrics clinical guidelines, the recommendations will be reviewed www.pediatrics.org/cgi/doi/10.1542/peds.2011-1330 routinely and incorporate new evidence, such as data from the Ran- doi:10.1542/peds.2011-1330 domized Intervention for Children With Vesicoureteral Reflux (RIVUR) study. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2011 by the American Academy of Pediatrics CONCLUSIONS: Changes in this revision include criteria for the diag- COMPANION PAPERS: Companions to this article can be found nosis of UTI and recommendations for imaging. Pediatrics 2011;128: on pages 572 and e749, and online at www.pediatrics.org/cgi/ 595–610 doi/10.1542/peds.2011-1818 and www.pediatrics.org/cgi/doi/10. 1542/peds.2011-1332. PEDIATRICS Volume 128, Number 3, September 2011 595 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 3. INTRODUCTION for use in a variety of clinical settings ness of prophylactic antimicrobial Since the early 1970s, occult bactere- (eg, office, emergency department, or therapy to prevent recurrence of fe- mia has been the major focus of con- hospital) by clinicians who treat in- brile UTI/pyelonephritis in children cern for clinicians evaluating febrile fants and young children. This text is a with vesicoureteral reflux (VUR). The infants who have no recognizable summary of the analysis. The data on latter was based on the new and grow- source of infection. With the introduc- which the recommendations are ing body of evidence questioning the tion of effective conjugate vaccines based are included in a companion effectiveness of antimicrobial prophy- against Haemophilus influenzae type technical report.4 laxis to prevent recurrent febrile UTI in b and Streptococcus pneumoniae Like the 1999 practice parameter, this children with VUR. To explore this par- (which have resulted in dramatic de- revision focuses on the diagnosis and ticular issue, the literature search was creases in bacteremia and meningi- management of initial urinary tract in- expanded to include trials published tis), there has been increasing appre- fections (UTIs) in febrile infants and since 1993 in which antimicrobial pro- ciation of the urinary tract as the most young children (2–24 months of age) phylaxis was compared with no treat- frequent site of occult and serious bac- who have no obvious neurologic or an- ment or placebo treatment for chil- terial infections. Because the clinical atomic abnormalities known to be as- dren with VUR. Because all except 1 of presentation tends to be nonspecific in sociated with recurrent UTI or renal the recent randomized controlled tri- infants and reliable urine specimens damage. (For simplicity, in the remain- als (RCTs) of the effectiveness of pro- for culture cannot be obtained without der of this guideline the phrase “fe- phylaxis included children more than invasive methods (urethral cathe- brile infants” is used to indicate febrile 24 months of age and some did not terization or suprapubic aspiration infants and young children 2–24 provide specific data according to [SPA]), diagnosis and treatment may months of age.) The lower and upper grade of VUR, the authors of the 6 RCTs be delayed. Most experimental and age limits were selected because stud- were contacted; all provided raw data clinical data support the concept that ies on infants with unexplained fever from their studies specifically ad- delays in the institution of appropriate generally have used these age limits dressing infants 2 to 24 months of age, treatment of pyelonephritis increase and have documented that the preva- according to grade of VUR. Meta- the risk of renal damage.1,2 lence of UTI is high (ϳ5%) in this age analysis of these data was performed. This clinical practice guideline is a re- group. In those studies, fever was de- Results from the literature searches vision of the practice parameter pub- fined as temperature of at least 38.0°C and meta-analyses were provided to lished by the American Academy of (Ն100.4°F); accordingly, this definition committee members. Issues were Pediatrics (AAP) in 1999.3 It was devel- of fever is used in this guideline. Ne- raised and discussed until consensus oped by a subcommittee of the Steer- onates and infants less than 2 was reached regarding recommenda- ing Committee on Quality Improvement months of age are excluded, because tions. The quality of evidence support- and Management that included physi- there are special considerations in ing each recommendation and the cians with expertise in the fields of ac- this age group that may limit the ap- strength of the recommendation were ademic general pediatrics, epidemiol- plication of evidence derived from assessed by the committee member ogy and informatics, pediatric the studies of 2- to 24-month-old chil- most experienced in informatics and infectious diseases, pediatric nephrol- dren. Data are insufficient to deter- epidemiology and were graded ac- ogy, pediatric practice, pediatric radi- mine whether the evidence gener- cording to AAP policy5 (Fig 1). ology, and pediatric urology. The AAP ated from studies of infants 2 to 24 The subcommittee formulated 7 rec- funded the development of this guide- months of age applies to children ommendations, which are presented line; none of the participants had any more than 24 months of age. in the text in the order in which a clini- financial conflicts of interest. The cian would use them when evaluating guideline was reviewed by multiple METHODS and treating a febrile infant, as well as groups within the AAP (7 committees, 1 To provide evidence for the guideline, 2 in algorithm form in the Appendix. This council, and 9 sections) and 5 external literature searches were conducted, clinical practice guideline is not in- organizations in the United States and that is, a surveillance of Medline-listed tended to be a sole source of guidance Canada. The guideline will be reviewed literature over the past 10 years for for the treatment of febrile infants with and/or revised in 5 years, unless new significant changes since the guideline UTIs. Rather, it is intended to assist clini- evidence emerges that warrants revi- was published and a systematic re- cians in decision-making. It is not in- sion sooner. The guideline is intended view of the literature on the effective- tended to replace clinical judgment or to 596 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 4. FROM THE AMERICAN ACADEMY OF PEDIATRICS tainer, because they may be contami- nated by bacteria in the distal urethra. Cultures of urine specimens collected in a bag applied to the perineum have an unacceptably high false-positive rate and are valid only when they yield negative results.6,14–16 With a preva- lence of UTI of 5% and a high rate of false-positive results (specificity: ϳ63%), a “positive” culture result for FIGURE 1 urine collected in a bag would be a AAP evidence strengths. false-positive result 88% of the time. For febrile boys, with a prevalence of UTI of 2%, the rate of false-positive re- establish an exclusive protocol for the administered, because the antimicro- sults is 95%; for circumcised boys, care of all children with this condition. bial agents commonly prescribed in with a prevalence of UTI of 0.2%, the such situations would almost certainly rate of false-positive results is 99%. DIAGNOSIS obscure the diagnosis of UTI. Therefore, in cases in which antimicro- Action Statement 1 SPA has been considered the standard bial therapy will be initiated, catheter- If a clinician decides that a febrile method for obtaining urine that is un- ization or SPA is required to establish infant with no apparent source for contaminated by perineal flora. Vari- the diagnosis of UTI. the fever requires antimicrobial able success rates for obtaining urine ● Aggregate quality of evidence: A (diag- therapy to be administered be- have been reported (23%–90%).6–8 nostic studies on relevant populations). cause of ill appearance or another When ultrasonographic guidance is pressing reason, the clinician used, success rates improve.9,10 The ● Benefits: A missed diagnosis of UTI should ensure that a urine speci- technique has limited risks, but tech- can lead to renal scarring if left un- men is obtained for both culture nical expertise and experience are treated; overdiagnosis of UTI can and urinalysis before an antimicro- required, and many parents and phy- lead to overtreatment and unneces- bial agent is administered; the sicians perceive the procedure as sary and expensive imaging. Once an- specimen needs to be obtained unacceptably invasive, compared timicrobial therapy is initiated, the op- through catheterization or SPA, be- with catheterization. However, there portunity to make a definitive cause the diagnosis of UTI cannot may be no acceptable alternative to diagnosis is lost; multiple studies of be established reliably through cul- SPA for boys with moderate or se- antimicrobial therapy have shown ture of urine collected in a bag vere phimosis or girls with tight la- that the urine may be rapidly (evidence quality: A; strong bial adhesions. sterilized. recommendation). Urine obtained through catheteriza- ● Harms/risks/costs: Catheterization When evaluating febrile infants, clini- tion for culture has a sensitivity of 95% is invasive. cians make a subjective assessment of and a specificity of 99%, compared ● Benefit-harms assessment: Prepon- the degree of illness or toxicity, in ad- with that obtained through SPA.7,11,12 derance of benefit over harm. dition to seeking an explanation for the The techniques required for catheter- ● Value judgments: Once antimicro- fever. This clinical assessment deter- ization and SPA are well described.13 bial therapy has begun, the opportu- mines whether antimicrobial therapy When catheterization or SPA is being attempted, the clinician should have a nity to make a definitive diagnosis is should be initiated promptly and af- sterile container ready to collect a lost. Therefore, it is important to fects the diagnostic process regarding UTI. If the clinician determines that the urine specimen, because the prepara- have the most-accurate test for UTI degree of illness warrants immediate tion for the procedure may stimulate performed initially. antimicrobial therapy, then a urine the child to void. Whether the urine is ● Role of patient preferences: There is specimen suitable for culture should obtained through catheterization or is no evidence regarding patient pref- be obtained through catheterization or voided, the first few drops should be erences for bag versus catheterized SPA before antimicrobial agents are allowed to fall outside the sterile con- urine. However, bladder tap has PEDIATRICS Volume 128, Number 3, September 2011 597 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 5. been shown to be more painful than urethral catheterization. ● Exclusions: None. ● Intentional vagueness: The basis of the determination that antimicro- bial therapy is needed urgently is not specified, because variability in clinical judgment is expected; con- siderations for individual patients, such as availability of follow-up care, may enter into the decision, FIGURE 2 and the literature provides only gen- Probability of UTI Among Febrile Infant Girls28 and Infant Boys30 According to Number of Findings Present. aProbability of UTI exceeds 1% even with no risk factors other than being uncircumcised. eral guidance. ● Policy level: Strong recommendation. be obtained through catheteriza- than 1% for 10.4% of academicians and Action Statement 2 tion or SPA and cultured; if urinaly- 11.7% for practitioners26; when the If a clinician assesses a febrile infant sis of fresh (<1 hour since void) threshold was increased to 1% to 3%, with no apparent source for the fever urine yields negative leukocyte es- 67.5% of academicians and 45.7% of as not being so ill as to require imme- terase and nitrite test results, then practitioners considered the yield suf- diate antimicrobial therapy, then the it is reasonable to monitor the clin- ficiently high to warrant urine culture. clinician should assess the likelihood of ical course without initiating anti- Therefore, attempting to operational- UTI (see below for how to assess microbial therapy, recognizing that ize “low likelihood” (ie, below a thresh- likelihood). negative urinalysis results do not old that warrants a urine culture) does rule out a UTI with certainty. not produce an absolute percentage; Action Statement 2a If the clinician determines that the de- clinicians will choose a threshold de- If the clinician determines the febrile gree of illness does not require imme- pending on factors such as their confi- infant to have a low likelihood of UTI diate antimicrobial therapy, then the dence that contact will be maintained (see text), then clinical follow-up likelihood of UTI should be assessed. through the illness (so that a specimen monitoring without testing is suffi- As noted previously, the overall preva- can be obtained at a later time) and com- cient (evidence quality: A; strong lence of UTI in febrile infants who have fort with diagnostic uncertainty. Fig 2 in- recommendation). no source for their fever evident on the dicates the number of risk factors as- basis of history or physical examina- sociated with threshold probabilities Action Statement 2b tion results is approximately 5%,17,18 of UTI of at least 1% and at least 2%. If the clinician determines that the but it is possible to identify groups In a series of studies, Gorelick, Shaw, febrile infant is not in a low-risk with higher-than-average likelihood and colleagues27–29 derived and vali- group (see below), then there are 2 and some with lower-than-average dated a prediction rule for febrile in- choices (evidence quality: A; strong likelihood. The prevalence of UTI fant girls on the basis of 5 risk factors, recommendation). Option 1 is to ob- among febrile infant girls is more than namely, white race, age less than 12 tain a urine specimen through cath- twice that among febrile infant boys months, temperature of at least 39°C, eterization or SPA for culture and (relative risk: 2.27). The rate for uncir- fever for at least 2 days, and absence urinalysis. Option 2 is to obtain a cumcised boys is 4 to 20 times higher of another source of infection. This urine specimen through the most than that for circumcised boys, whose prediction rule, with sensitivity of convenient means and to perform a rate of UTI is only 0.2% to 0.4%.19–24 The 88% and specificity of 30%, permits urinalysis. If the urinalysis results presence of another, clinically obvious some infant girls to be considered in suggest a UTI (positive leukocyte source of infection reduces the likeli- a low-likelihood group (Fig 2). For ex- esterase test results or nitrite test hood of UTI by one-half.25 ample, of girls with no identifiable or microscopic analysis results In a survey asking, “What yield is re- source of infection, those who are non- positive for leukocytes or bacte- quired to warrant urine culture in fe- white and more than 12 months of age ria), then a urine specimen should brile infants?,” the threshold was less with a recent onset (Ͻ2 days) of low- 598 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 6. FROM THE AMERICAN ACADEMY OF PEDIATRICS grade fever (Ͻ39°C) have less than a TABLE 1 Sensitivity and Specificity of Components of Urinalysis, Alone and in Combination 1% probability of UTI; each additional Test Sensitivity (Range), % Specificity (Range), % risk factor increases the probability. It Leukocyte esterase test 83 (67–94) 78 (64–92) Nitrite test 53 (15–82) 98 (90–100) should be noted, however, that some Leukocyte esterase or 93 (90–100) 72 (58–91) of the factors (eg, duration of fever) nitrite test positive may change during the course of the Microscopy, WBCs 73 (32–100) 81 (45–98) Microscopy, bacteria 81 (16–99) 83 (11–100) illness, excluding the infant from a Leukocyte esterase test, 99.8 (99–100) 70 (60–92) low-likelihood designation and nitrite test, or prompting testing as described in microscopy positive action statement 2a. As demonstrated in Fig 2, the major definitive urine specimen through Action Statement 3 risk factor for febrile infant boys is catheterization initially. whether they are circumcised. The prob- To establish the diagnosis of UTI, ● Aggregate quality of evidence: A (diag- clinicians should require both uri- ability of UTI can be estimated on the ba- nostic studies on relevant populations). nalysis results that suggest infec- sis of 4 risk factors, namely, nonblack race, temperature of at least 39°C, fever ● Benefits: Accurate diagnosis of UTI tion (pyuria and/or bacteriuria) can prevent the spread of infection and the presence of at least 50 000 for more than 24 hours, and absence of and renal scarring; avoiding overdi- colony-forming units (CFUs) per mL another source of infection.4,30 agnosis of UTI can prevent over- of a uropathogen cultured from a If the clinician determines that the in- treatment and unnecessary and ex- urine specimen obtained through fant does not require immediate anti- pensive imaging. catheterization or SPA (evidence microbial therapy and a urine speci- quality: C; recommendation). ● Harms/risks/costs: A small propor- men is desired, then often a urine tion of febrile infants, considered at collection bag affixed to the perineum Urinalysis low likelihood of UTI, will not receive is used. Many clinicians think that this timely identification and treatment General Considerations collection technique has a low contam- of their UTIs. ination rate under the following cir- Urinalysis cannot substitute for urine ● Benefit-harms assessment: Prepon- culture to document the presence of cumstances: the patient’s perineum is derance of benefit over harm. UTI but needs to be used in conjunction properly cleansed and rinsed before application of the collection bag, the ● Value judgments: There is a risk of with culture. Because urine culture re- UTI sufficiently low to forestall fur- sults are not available for at least 24 urine bag is removed promptly after ther evaluation. hours, there is considerable interest urine is voided into the bag, and the ● Role of patient preferences: The in tests that may predict the results of specimen is refrigerated or processed choice of option 1 or option 2 and the urine culture and enable presump- immediately. Even if contamination the threshold risk of UTI warranting tive therapy to be initiated at the first from the perineal skin is minimized, obtaining a urine specimen may be encounter. Urinalysis can be per- however, there may be significant con- formed on any specimen, including tamination from the vagina in girls or influenced by parents’ preference to avoid urethral catheterization (if one collected from a bag applied to the the prepuce in uncircumcised boys, perineum. However, the specimen the 2 groups at highest risk of UTI. A a bag urine sample yields negative urinalysis results) versus timely must be fresh (Ͻ1 hour after voiding “positive” culture result from a speci- with maintenance at room tempera- evaluation (obtaining a definitive men collected in a bag cannot be used ture or Ͻ4 hours after voiding with re- specimen through catheterization). to document a UTI; confirmation re- frigeration), to ensure sensitivity and quires culture of a specimen collected ● Exclusions: Because it depends on a specificity of the urinalysis. The tests through catheterization or SPA. Be- range of patient- and physician- that have received the most atten- cause there may be substantial delay specific considerations, the precise tion are biochemical analyses of leu- waiting for the infant to void and a sec- threshold risk of UTI warranting ob- kocyte esterase and nitrite through a ond specimen, obtained through cath- taining a urine specimen is left to rapid dipstick method and urine eterization, may be necessary if the the clinician but is below 3%. microscopic examination for white urinalysis suggests the possibility of ● Intentional vagueness: None. blood cells (WBCs) and bacteria UTI, many clinicians prefer to obtain a ● Policy level: Strong recommendation. (Table 1). PEDIATRICS Volume 128, Number 3, September 2011 599 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 7. Urine dipsticks are appealing, because 64%–92%]) generally is not as good as during infancy. In a study of infants 2 to they provide rapid results, do not re- the sensitivity, which reflects the non- 24 months of age, 0.7% of afebrile girls quire microscopy, and are eligible for specificity of pyuria in general. Accord- had 3 successive urine cultures with a waiver under the Clinical Laboratory ingly, positive leukocyte esterase test 105 CFUs per mL of a single uropatho- Improvement Amendments. They indi- results should be interpreted with cau- gen.26 Asymptomatic bacteriuria can cate the presence of leukocyte es- tion, because false-positive results are be easily confused with true UTI in a terase (as a surrogate marker for common. With numerous conditions febrile infant but needs to be distin- pyuria) and urinary nitrite (which is other than UTI, including fever result- guished, because studies suggest that converted from dietary nitrates in the ing from other conditions (eg, strepto- antimicrobial treatment may do more presence of most Gram-negative enteric coccal infections or Kawasaki dis- harm than good.36 The key to distin- bacteria in the urine). The conversion of ease), and after vigorous exercise, guishing true UTI from asymptomatic dietary nitrates to nitrites by bacteria re- WBCs may be found in the urine. There- bacteriuria is the presence of pyuria. quires approximately 4 hours in the fore, a finding of pyuria by no means bladder.31 The performance characteris- Microscopic Analysis for Bacteriuria confirms that an infection of the uri- tics of both leukocyte esterase and ni- nary tract is present. The presence of bacteria in a fresh, trite tests vary according to the defini- Gram-stained specimen of uncentri- The absence of pyuria in children with tion used for positive urine culture fuged urine correlates with 105 CFUs true UTIs is rare, however. It is theoret- results, the age and symptoms of the per mL in culture.37 An “enhanced uri- ically possible if a febrile child is as- population being studied, and the nalysis,” combining the counting sessed before the inflammatory re- method of urine collection. chamber assessment of pyuria noted sponse has developed, but the previously with Gram staining of drops Nitrite Test inflammatory response to a UTI pro- of uncentrifuged urine, with a thresh- duces both fever and pyuria; therefore, A nitrite test is not a sensitive marker old of at least 1 Gram-negative rod in for children, particularly infants, who children who are being evaluated be- 10 oil immersion fields, has greater sen- empty their bladders frequently. cause of fever should already have sitivity, specificity, and positive predic- Therefore, negative nitrite test results WBCs in their urine. More likely expla- tive value than does the standard urinal- have little value in ruling out UTI. More- nations for significant bacteriuria in ysis33 and is the preferred method of over, not all urinary pathogens reduce culture in the absence of pyuria in- urinalysis when appropriate equipment nitrate to nitrite. The test is helpful clude contaminated specimens, insen- and personnel are available. when the result is positive, however, sitive criteria for pyuria, and asymp- because it is highly specific (ie, there tomatic bacteriuria. In most cases, Automated Urinalysis are few false-positive results).32 when true UTI has been reported to oc- Automated methods to perform uri- cur in the absence of pyuria, the defi- nalysis are now being used in many Leukocyte Esterase Test nition of pyuria has been at fault. The hospitals and laboratories. Image- The sensitivity of the leukocyte es- standard method of assessing pyuria based systems use flow imaging terase test is 94% when it used in the has been centrifugation of the urine analysis technology and software to context of clinically suspected UTI. and microscopic analysis, with a classify particles in uncentrifuged Overall, the reported sensitivity in var- threshold of 5 WBCs per high-power urine specimens rapidly.38 Results ious studies is lower (83%), because field (ϳ25 WBCs per ␮L). If a counting correlate well with manual methods, the results of leukocyte esterase tests chamber is used, however, the finding especially for red blood cells, WBCs, were related to culture results without of at least 10 WBCs per ␮L in uncentri- and squamous epithelial cells. In the exclusion of individuals with asymp- fuged urine has been demonstrated to future, this may be the most common tomatic bacteriuria. The absence of be more sensitive33 and performs well method by which urinalysis is per- leukocyte esterase in the urine of indi- in clinical situations in which the stan- formed in laboratories. viduals with asymptomatic bacteriuria dard method does not, such as with is an advantage of the test, rather than very young infants.34 Culture a limitation, because it distinguishes An important cause of bacteriuria in The diagnosis of UTI is made on the ba- individuals with asymptomatic bacte- the absence of pyuria is asymptomatic sis of quantitative urine culture re- riuria from those with true UTI. bacteriuria. Asymptomatic bacteriuria sults in addition to evidence of pyuria The specificity of the leukocyte es- often is associated with school-aged and/or bacteriuria. Urine specimens terase test (average: 72% [range: and older girls,35 but it can be present should be processed as expediently as 600 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 8. FROM THE AMERICAN ACADEMY OF PEDIATRICS possible. If the specimen is not pro- spp are not considered clinically rele- ● Harms/risks/costs: Stringent diag- cessed promptly, then it should be re- vant urine isolates for otherwise nostic criteria may miss a small frigerated to prevent the growth of or- healthy, 2- to 24-month-old children.) number of UTIs. ganisms that can occur in urine at Reducing the threshold from 100 000 ● Benefit-harms assessment: Prepon- room temperature; for the same rea- CFUs per mL to 50 000 CFUs per mL derance of benefit over harm. son, specimens that require transpor- would seem to increase the sensitivity ● Value judgments: Treatment of tation to another site for processing of culture at the expense of decreased asymptomatic bacteriuria may be should be transported on ice. A prop- specificity; however, because the pro- harmful. erly collected urine specimen should posed criteria for UTI now include evi- dence of pyuria in addition to positive ● Role of patient preferences: We as- be inoculated on culture medium that culture results, infants with “positive” sume that parents prefer no action will allow identification of urinary tract culture results alone will be recog- in the absence of a UTI (avoiding pathogens. nized as having asymptomatic bacteri- false-positive results) over a very Urine culture results are considered small chance of missing a UTI. uria rather than a true UTI. Some labo- positive or negative on the basis of the ratories report growth only in the ● Exclusions: None. number of CFUs that grow on the cul- ture medium.36 Definition of significant following categories: 0 to 1000, 1000 to ● Intentional vagueness: None. 10 000, 10 000 to 100 000, and more ● Policy level: Recommendation. colony counts with regard to the than 100 000 CFUs per mL. In such method of collection considers that cases, results in the 10 000 to 100 000 MANAGEMENT the distal urethra and periurethral CFUs per mL range need to be evalu- area are commonly colonized by the Action Statement 4 ated in context, such as whether the same bacteria that may cause UTI; urinalysis findings support the diagno- Action Statement 4a therefore, a low colony count may be sis of UTI and whether the organism is present in a specimen obtained When initiating treatment, the clini- a recognized uropathogen. through voiding or catheterization cian should base the choice of when bacteria are not present in blad- Alternative culture methods, such as route of administration on practi- der urine. Definitions of positive and dipslides, may have a place in the of- cal considerations. Initiating treat- negative culture results are opera- fice setting; sensitivity is reported to ment orally or parenterally is tional and not absolute. The time the be in the range of 87% to 100%, and equally efficacious. The clinician urine resides in the bladder (bladder specificity is reported to be 92% to should base the choice of agent on incubation time) is an important deter- 98%, but dipslides cannot specify the local antimicrobial sensitivity pat- minant of the magnitude of the colony organism or antimicrobial sensitivi- terns (if available) and should ad- ties.41 Practices that use dipslides just the choice according to sensi- count. The concept that more than should do so in collaboration with a tivity testing of the isolated 100 000 CFUs per mL indicates a UTI certified laboratory for identification uropathogen (evidence quality: A; was based on morning collections of and sensitivity testing or, in the ab- strong recommendation). urine from adult women, with compar- sence of such results, may need to per- ison of specimens from women with- form “test of cure” cultures after 24 Action Statement 4b out symptoms and women considered hours of treatment. The clinician should choose 7 to 14 clinically to have pyelonephritis; the transition range, in which the propor- ● Aggregate quality of evidence: C (ob- days as the duration of antimicrobial tion of women with pyelonephritis ex- servational studies). therapy (evidence quality: B; ceeded the proportion of women with- ● Benefits: Accurate diagnosis of UTI recommendation). out symptoms, was 10 000 to 100 000 can prevent the spread of infection The goals of treatment of acute UTI are CFUs per mL.39 In most instances, an and renal scarring; avoiding overdi- to eliminate the acute infection, to pre- appropriate threshold to consider agnosis of UTI can prevent over- vent complications, and to reduce the bacteriuria “significant” in infants and treatment and unnecessary and ex- likelihood of renal damage. Most chil- children is the presence of at least pensive imaging. These criteria dren can be treated orally.42–44 Patients 50 000 CFUs per mL of a single urinary reduce the likelihood of overdiagno- whom clinicians judge to be “toxic” or pathogen.40 (Organisms such as sis of UTI in infants with asymptom- who are unable to retain oral intake Lactobacillus spp, coagulase-negative atic bacteriuria or contaminated (including medications) should re- staphylococci, and Corynebacterium specimens. ceive an antimicrobial agent parenter- PEDIATRICS Volume 128, Number 3, September 2011 601 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 9. TABLE 2 Some Empiric Antimicrobial Agents TABLE 3 Some Empiric Antimicrobial Agents for Oral Treatment of UTI for Parenteral Treatment of UTI Antimicrobial Agent Dosage Antimicrobial Dosage Amoxicillin-clavulanate 20–40 mg/kg per d in 3 doses Agent Sulfonamide Ceftriaxone 75 mg/kg, every 24 h Trimethoprim-sulfamethoxazole 6–12 mg/kg trimethoprim and 30-60 mg/kg sulfamethoxazole Cefotaxime 150 mg/kg per d, per d in 2 doses divided every 6–8 h Sulfisoxazole 120–150 mg/kg per d in 4 doses Ceftazidime 100–150 mg/kg per d, Cephalosporin divided every 8 h Cefixime 8 mg/kg per d in 1 dose Gentamicin 7.5 mg/kg per d, Cefpodoxime 10 mg/kg per d in 2 doses divided every 8 h Cefprozil 30 mg/kg per d in 2 doses Tobramycin 5 mg/kg per d, Cefuroxime axetil 20–30 mg/kg per d in 2 doses divided every 8 h Cephalexin 50–100 mg/kg per d in 4 doses Piperacillin 300 mg/kg per d, divided every 6–8 h the total course of therapy should be 7 distinguishes the benefit of treating ally (Table 2) until they exhibit clinical to 14 days. The committee attempted to 7 vs 10 vs 14 days, and the range is improvement, generally within 24 to 48 identify a single, preferred, evidence- allowable. hours, and are able to retain orally ad- based duration, rather than a range, but ● Policy level: Strong recommendation/ ministered fluids and medications. In a data comparing 7, 10, and 14 days di- study of 309 febrile infants with UTIs, recommendation. rectly were not found. There is evidence only 3 (1%) were deemed too ill to be that 1- to 3-day courses for febrile UTIs Action Statement 5 assigned randomly to either paren- are inferior to courses in the recom- teral or oral treatment.42 Parenteral Febrile infants with UTIs should mended range; therefore, the minimal administration of an antimicrobial undergo renal and bladder ultra- duration selected should be 7 days. agent also should be considered when sonography (RBUS) (evidence ● Aggregate quality of evidence: A/B quality: C; recommendation). compliance with obtaining an antimi- crobial agent and/or administering it (RCTs). The purpose of RBUS is to detect ana- orally is uncertain. The usual choices ● Benefits: Adequate treatment of UTI tomic abnormalities that require fur- for oral treatment of UTIs include can prevent the spread of infection ther evaluation, such as additional im- a cephalosporin, amoxicillin plus and renal scarring. Outcomes of aging or urologic consultation. RBUS clavulanic acid, or trimethoprim- short courses (1–3 d) are inferior to also provides an evaluation of the re- sulfamethoxazole (Table 3). It is essen- those of 7- to 14-d courses. nal parenchyma and an assessment of tial to know local patterns of suscepti- ● Harms/risks/costs: There are mini- renal size that can be used to monitor bility of coliforms to antimicrobial mal harm and minor cost effects of renal growth. The yield of actionable agents, particularly trimethoprim- antimicrobial choice and duration findings is relatively low.45,46 Wide- sulfamethoxazole and cephalexin, be- of therapy. spread application of prenatal ultra- cause there is substantial geographic ● Benefit-harms assessment: Prepon- sonography clearly has reduced the variability that needs to be taken into derance of benefit over harm. prevalence of previously unsuspected account during selection of an antimi- obstructive uropathy in infants, but the ● Value judgments: Adjusting antimi- crobial agent before sensitivity results consequences of prenatal screening crobial choice on the basis of avail- are available. Agents that are excreted with respect to the risk of renal abnor- able data and treating according to in the urine but do not achieve thera- malities in infants with UTIs have not best evidence will minimize cost and peutic concentrations in the blood- yet been well defined. There is consid- consequences of failed or unneces- stream, such as nitrofurantoin, should erable variability in the timing and sary treatment. not be used to treat febrile infants with quality of prenatal ultrasonograms, UTIs, because parenchymal and serum ● Role of patient preferences: It is as- and the report of “normal” ultrasono- antimicrobial concentrations may be sumed that parents prefer the graphic results cannot necessarily be insufficient to treat pyelonephritis or most-effective treatment and the relied on to dismiss completely the urosepsis. least amount of medication that en- possibility of a structural abnormality sures effective treatment. Whether the initial route of administra- unless the study was a detailed ana- tion of the antimicrobial agent is oral ● Exclusions: None. tomic survey (with measurements), or parenteral (then changed to oral), ● Intentional vagueness: No evidence was performed during the third tri- 602 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 10. FROM THE AMERICAN ACADEMY OF PEDIATRICS mester, and was performed and inter- children with reduced renal function. Action Statement 6 preted by qualified individuals.47 The radiation dose from dimercapto- Action Statement 6a The timing of RBUS depends on the succinic acid is additive with that of VCUG should not be performed clinical situation. RBUS is recom- VCUG when both studies are per- routinely after the first febrile mended during the first 2 days of treat- formed.50 The radiation dose from UTI; VCUG is indicated if RBUS re- ment to identify serious complications, VCUG depends on the equipment that veals hydronephrosis, scarring, such as renal or perirenal abscesses is used (conventional versus pulsed or other findings that would sug- or pyonephrosis associated with ob- digital fluoroscopy) and is related di- gest either high-grade VUR or ob- structive uropathy when the clinical ill- rectly to the total fluoroscopy time. structive uropathy, as well as in ness is unusually severe or substantial Moreover, the total exposure for the other atypical or complex clinical clinical improvement is not occurring. child will be increased when both circumstances (evidence quality For febrile infants with UTIs who dem- acute and follow-up studies are ob- B; recommendation). onstrate substantial clinical improve- tained. The lack of exposure to radi- ment, however, imaging does not need ation is a major advantage of RBUS, Action Statement 6b to occur early during the acute infec- even with recognition of the limita- Further evaluation should be con- tion and can even be misleading; ani- tions of this modality that were de- ducted if there is a recurrence of fe- mal studies demonstrate that Esche- scribed previously. brile UTI (evidence quality: X; richia coli endotoxin can produce recommendation). ● Aggregate quality of evidence: C (ob- dilation during acute infection, which servational studies). For the past 4 decades, the strategy to could be confused with hydronephro- ● Benefits: RBUS in this population protect the kidneys from further dam- sis, pyonephrosis, or obstruction.48 age after an initial UTI has been to de- Changes in the size and shape of the will yield abnormal results in ϳ15% tect childhood genitourinary abnor- kidneys and the echogenicity of renal of cases, and 1% to 2% will have ab- malities in which recurrent UTI could parenchyma attributable to edema normalities that would lead to ac- increase renal damage. The most com- also are common during acute infec- tion (eg, additional evaluation, re- mon of these is VUR, and VCUG is used tion. The presence of these abnormal- ferral, or surgery). to detect this. Management included ities makes it inappropriate to con- ● Harms/risks/costs: Between 2% continuous antimicrobial administra- sider RBUS performed early during and 3% will be false-positive results, tion as prophylaxis and surgical inter- acute infection to be a true baseline leading to unnecessary and invasive vention if VUR was persistent or recur- study for later comparisons in the as- evaluations. rences of infection were not prevented sessment of renal growth. with an antimicrobial prophylaxis reg- ● Benefit-harms assessment: Prepon- Nuclear scanning with technetium- derance of benefit over harm. imen; some have advocated surgical labeled dimercaptosuccinic acid has intervention to correct high-grade re- ● Value judgments: The seriousness greater sensitivity for detection of flux even when infection has not re- acute pyelonephritis and later scar- of the potentially correctable abnor- curred. However, it is clear that there ring than does either RBUS or voiding malities in 1% to 2%, coupled with are a significant number of infants cystourethrography (VCUG). The scan- the absence of physical harm, was who develop pyelonephritis in whom ning is useful in research, because it judged sufficiently important to tip VUR cannot be demonstrated, and the ensures that all subjects in a study the scales in favor of testing. effectiveness of antimicrobial prophy- have pyelonephritis to start with and it ● Role of patient preferences: Be- laxis for patients who have VUR has permits assessment of later renal cause ultrasonography is noninva- been challenged in the past decade. scarring as an outcome measure. The sive and poses minimal risk, we as- Several studies have suggested that findings on nuclear scans rarely affect sume that parents will prefer RBUS prophylaxis does not confer the de- acute clinical management, however, over taking even a small risk of sired benefit of preventing recurrent and are not recommended as part of missing a serious and correctable febrile UTI.51–55 If prophylaxis is, in fact, routine evaluation of infants with their condition. not beneficial and VUR is not required first febrile UTI. The radiation dose to for development of pyelonephritis, ● Exclusions: None. the patient during dimercaptosuccinic then the rationale for performing acid scanning is generally low (ϳ1 ● Intentional vagueness: None. VCUG routinely after an initial febrile mSv),49 although it may be increased in ● Policy level: Recommendation. UTI must be questioned. PEDIATRICS Volume 128, Number 3, September 2011 603 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 11. RCTs of the effectiveness of prophy- TABLE 4 Recurrences of Febrile UTI/Pyelonephritis in Infants 2 to 24 Months of Age With and Without Antimicrobial Prophylaxis, According to Grade of VUR laxis performed to date generally in- Reflux Prophylaxis No Prophylaxis P cluded children more than 24 months Grade of age, and some did not provide com- No. of Total N No. of Total N Recurrences Recurrences plete data according to grade of VUR. None 7 210 11 163 .15 These 2 factors have compromised I 2 37 2 35 1.00 meta-analyses. To ensure direct com- II 11 133 10 124 .95 parisons, the committee contacted the III 31 140 40 145 .29 IV 16 55 21 49 .14 6 researchers who had conducted the most recent RCTs and requested raw data from their studies.51–56 All com- the initial UTI, those who have the ● Benefits: This avoids, for the vast plied, which permitted the creation of greatest likelihood of having high- majority of febrile infants with UTIs, a data set with data for 1091 infants 2 grade VUR. Unfortunately, there are no radiation exposure (of particular to 24 months of age according to grade clinical or laboratory indicators that concern near the ovaries in girls), of VUR. A ␹2 analysis (2-tailed) and a have been demonstrated to identify in- expense, and discomfort. formal meta-analysis did not detect a fants with high-grade VUR. Indications ● Harms/risks/costs: Detection of a statistically significant benefit of pro- for VCUG have been proposed on the small number of cases of high- phylaxis in preventing recurrence of basis of consensus in the absence of grade reflux and correctable abnor- febrile UTI/pyelonephritis in infants data57; the predictive value of any of the malities is delayed. without reflux or those with grades I, II, indications for VCUG proposed in this manner is not known. ● Benefit-harms assessment: Prepon- III, or IV VUR (Table 4 and Fig 3). Only 5 derance of benefit over harm. infants with grade V VUR were in- The level of evidence supporting rou- tine imaging with VCUG was deemed ● Value judgments: The risks associ- cluded in the RCTs; therefore, data for insufficient at the time of the 1999 ated with radiation (plus the ex- those infants are not included in Table practice parameter to receive a rec- pense and discomfort of the proce- 4 or Fig 3. ommendation, but the consensus of dure) for the vast majority of infants The proportion of infants with high- outweigh the risk of delaying the de- the subcommittee was to “strongly en- grade VUR among all infants with fe- tection of the few with correctable courage” imaging studies. The position brile UTIs is small. Data adapted from abnormalities until their second UTI. of the current subcommittee reflects current studies (Table 5) indicate that, the new evidence demonstrating anti- ● Role of patient preferences: The of a hypothetical cohort of 100 infants microbial prophylaxis not to be effec- judgment of parents may come into with febrile UTIs, only 1 has grade V tive as presumed previously. More- play, because VCUG is an uncomfort- VUR; 99 do not. With a practice of wait- over, prompt diagnosis and effective able procedure involving radiation ing for a second UTI to perform VCUG, treatment of a febrile UTI recurrence exposure. In some cases, parents only 10 of the 100 would need to un- may be of greater importance regard- dergo the procedure and the 1 with may prefer to subject their children less of whether VUR is present or the to the procedure even when the grade V VUR would be identified. (It child is receiving antimicrobial pro- also is possible that the 1 infant with chance of benefit is both small and phylaxis. A national study (the Ran- uncertain. Antimicrobial prophy- grade V VUR might have been identified domized Intervention for Children With after the first UTI on the basis of abnor- laxis seems to be ineffective in pre- Vesicoureteral Reflux study) is cur- venting recurrence of febrile UTI/py- mal RBUS results that prompted VCUG rently in progress to identify the ef- to be performed.) Data to quantify ad- elonephritis for the vast majority of fects of a prophylactic antimicrobial ditional potential harm to an infant infants. Some parents may want to regimen for children 2 months to 6 who is not revealed to have high-grade avoid VCUG even after the second years of age who have experienced a VUR until a second UTI are not precise UTI. Because the benefit of identify- UTI, and it is anticipated to provide ad- but suggest that the increment is in- ing high-grade reflux is still in some ditional important data58 (see Areas sufficient to justify routinely subject- doubt, these preferences should be for Research). ing all infants with an initial febrile UTI considered. It is the judgment of the to VCUG (Fig 4). To minimize any harm Action Statement 6a committee that VCUG is indicated af- incurred by that infant, attempts have ● Aggregate quality of evidence: B ter the second UTI. been made to identify, at the time of (RCTs). ● Exclusions: None. 604 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 12. FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 5 Rates of VUR According to Grade in Hypothetical Cohort of Infants After First UTI and After Recurrence Rate, % After First After UTI Recurrence (N ϭ 100) (N ϭ 10) No VUR 65 26 Grades I–III VUR 29 56 Grade IV VUR 5 12 Grade V VUR 1 6 FIGURE 4 Relationship between renal scarring and num- ber of bouts of pyelonephritis. Adapted from Jodal.59 ● Intentional vagueness: None. ● Policy level: Recommendation. Action Statement 6b ● Aggregate quality of evidence: X (ex- ceptional situation). ● Benefits: VCUG after a second UTI should identify infants with very high-grade reflux. ● Harms/risks/costs: VCUG is an un- comfortable, costly procedure that involves radiation, including to the ovaries of girls. ● Benefit-harms assessment: Prepon- FIGURE 3 derance of benefit over harm. A, Recurrences of febrile UTI/pyelonephritis in 373 infants 2 to 24 months of age without VUR, with and without antimicrobial prophylaxis (based on 3 studies; data provided by Drs Craig, Garin, and Mon- ● Value judgments: The committee tini). B, Recurrences of febrile UTI/pyelonephritis in 72 infants 2 to 24 months of age with grade I VUR, judged that patients with high- with and without antimicrobial prophylaxis (based on 4 studies; data provided by Drs Craig, Garin, Montini, and Roussey-Kesler). C, Recurrences of febrile UTI/pyelonephritis in 257 infants 2 to 24 grade reflux and other abnormali- months of age with grade II VUR, with and without antimicrobial prophylaxis (based on 5 studies; data ties may benefit from interventions provided by Drs Craig, Garin, Montini, Pennesi, and Roussey-Kesler). D, Recurrences of febrile UTI/ to prevent further scarring. Further pyelonephritis in 285 infants 2 to 24 months of age with grade III VUR, with and without antimicrobial prophylaxis (based on 6 studies; data provided by Drs Brandström, Craig, Garin, Montini, Pennesi, and studies of treatment for grade V Roussey-Kesler). E, Recurrences of febrile UTI/pyelonephritis in 104 infants 2 to 24 months of age with VUR are not underway and are un- grade IV VUR, with and without antimicrobial prophylaxis (based on 3 studies; data provided by Drs likely in the near future, because the Brandström, Craig, and Pennesi). M-H indicates Mantel-Haenszel; CI, confidence interval. condition is uncommon and ran- domization of treatment in this group generally has been consid- ered unethical. PEDIATRICS Volume 128, Number 3, September 2011 605 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 13. ● Role of patient preferences: As men- ● Aggregate quality of evidence: C (ob- first UTI is not recommended; VCUG is tioned previously, the judgment of servational studies). indicated if RBUS reveals hydrone- parents may come into play, be- ● Benefits: Studies suggest that early phrosis, scarring, or other findings cause VCUG is an uncomfortable treatment of UTI reduces the risk of that would suggest either high-grade procedure involving radiation expo- renal scarring. VUR or obstructive uropathy, as well as sure. In some cases, parents may in other atypical or complex clinical ● Harms/risks/costs: There may be prefer to subject their children to circumstances. VCUG also should be additional costs and inconvenience the procedure even when the performed if there is a recurrence of to parents with more-frequent visits chance of benefit is both small and febrile UTI. to the clinician for evaluation of uncertain. The benefits of treatment fever. of VUR remain unproven, but the AREAS FOR RESEARCH point estimates suggest a small po- ● Benefit-harms assessment: Prepon- derance of benefit over harm. One of the major values of a compre- tential benefit. Similarly, parents hensive literature review is the identi- may want to avoid VCUG even after ● Value judgments: None. fication of areas in which evidence is the second UTI. Because the benefit ● Role of patient preferences: Parents lacking. The following 8 areas are pre- of identifying high-grade reflux is will ultimately make the judgment to sented in an order that parallels the still in some doubt, these prefer- seek medical care. previous discussion. ences should be considered. It is the ● Exclusions: None. 1. The relationship between UTIs in in- judgment of the committee that ● Intentional vagueness: None. fants and young children and re- VCUG is indicated after the second ● Policy level: Recommendation. duced renal function in adults has UTI. been established but is not ● Exclusions: None. CONCLUSIONS well characterized in quantitative ● Intentional vagueness: Further eval- terms. The ideal prospective cohort The committee formulated 7 key action uation will likely start with VCUG but study from birth to 40 to 50 years of statements for the diagnosis and may entail additional studies de- age has not been conducted and is treatment of infants and young chil- pending on the findings. The details unlikely to be conducted. There- dren 2 to 24 months of age with UTI and of further evaluation are beyond the fore, estimates of undesirable unexplained fever. Strategies for diag- scope of this guideline. outcomes in adulthood, such as nosis and treatment depend on ● Policy level: Recommendation. whether the clinician determines that hypertension and end-stage renal antimicrobial therapy is warranted im- disease, are based on the mathe- Action Statement 7 matical product of probabilities mediately or can be delayed safely un- After confirmation of UTI, the cli- til urine culture and urinalysis results at several steps, each of which is nician should instruct parents or are available. Diagnosis is based on subject to bias and error. Other guardians to seek prompt medical the presence of pyuria and at least attempts at decision analysis and evaluation (ideally within 48 50 000 CFUs per mL of a single uro- thoughtful literature review have hours) for future febrile ill- pathogen in an appropriately collected recognized the same limitations. nesses, to ensure that recurrent specimen of urine; urinalysis alone Until recently, imaging tools avail- infections can be detected and does not provide a definitive diagnosis. able for assessment of the effects treated promptly (evidence qual- After 7 to 14 days of antimicrobial of UTIs have been insensitive. With ity: C; recommendation). treatment, close clinical follow-up the imaging techniques now avail- Early treatment limits renal damage monitoring should be maintained, with able, it may be possible to identify better than late treatment,1,2 and the evaluation of the urine during subse- the relationship of scarring to re- risk of renal scarring increases as the quent febrile episodes to permit nal impairment and hypertension. number of recurrences increase (Fig prompt diagnosis and treatment of re- 2. The development of techniques that 4).59 For these reasons, all infants who current infections. Ultrasonography of would permit an alternative to inva- have sustained a febrile UTI should the kidneys and bladder should be per- sive sampling and culture would be have a urine specimen obtained at the formed to detect anatomic abnormali- valuable for general use. Special at- onset of subsequent febrile illnesses, ties that require further evaluation tention should be given to infant so that a UTI can be diagnosed and (eg, additional imaging or urologic girls and uncircumcised boys, be- treated promptly. consultation). Routine VCUG after the cause urethral catheterization may 606 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on January 2, 2012
  • 14. FROM THE AMERICAN ACADEMY OF PEDIATRICS be difficult and can produce con- microbial resistance. To overcome the infants will have recurrent UTIs; taminated specimens and SPA now these issues, evidence of effective- some will be identified as having VUR is not commonly performed. Incu- ness with a well-tolerated, safe or other abnormalities. Further re- bation time, which is inherent in the product would be required, and search addressing the optimal culture process, results in delayed parents would need sufficient edu- course of management in specific sit- treatment or presumptive treat- cation to understand the value and uations would be valuable. ment on the basis of tests that lack importance of adherence. A urinary 8. The optimal duration of antimicro- the desired sensitivity and specific- antiseptic, rather than an antimi- bial treatment has not been deter- ity to replace culture. crobial agent, would be particularly mined. RCTs of head-to-head com- 3. The role of VUR (and therefore of desirable, because it could be taken parisons of various duration would VCUG) is incompletely understood. indefinitely without concern that be valuable, enabling clinicians to It is recognized that pyelonephritis bacteria would develop resistance. limit antimicrobial exposure to (defined through cortical scintigra- Another possible strategy might be what is needed to eradicate the of- phy) can occur in the absence of the use of probiotics. fending uropathogen. VUR (defined through VCUG) and 5. Better understanding of the ge- that progressive renal scarring nome (human and bacterial) may LEAD AUTHOR provide insight into risk factors Kenneth B. Roberts, MD (defined through cortical scintigra- phy) can occur in the absence of (VUR and others) that lead to in- SUBCOMMITTEE ON URINARY TRACT demonstrated VUR.52,53 The pre- creased scarring. Blood specimens INFECTION, 2009 –2011 sumption that antimicrobial pro- will be retained from children en- Kenneth B. Roberts, MD, Chair Stephen M. Downs, MD, MS phylaxis is of benefit for individuals rolled in the Randomized Interven- S. Maria E. Finnell, MD, MS with VUR to prevent recurrences of tion for Children With Vesi- Stanley Hellerstein, MD UTI or the development of renal scars coureteral Reflux study, for future Linda D. Shortliffe, MD examination of genetic determinants Ellen R. Wald, MD is not supported by the aggregate of J. Michael Zerin, MD data from recent studies and cur- of VUR, recurrent UTI, and renal scar- rently is the subject of the Random- ring.58 VUR is recognized to “run in OVERSIGHT BY THE STEERING ized Intervention for Children With families,”60,61 and multiple investiga- COMMITTEE ON QUALITY tors are currently engaged in re- IMPROVEMENT AND MANAGEMENT, Vesicoureteral Reflux study.58 search to identify a genetic basis for 2009 –2011 4. Although the effectiveness of anti- microbial prophylaxis for the pre- VUR. Studies may also be able to dis- STAFF tinguish the contribution of congeni- Caryn Davidson, MA vention of UTI has not been demon- tal dysplasia from acquired scarring strated, the concept has biological ACKNOWLEDGMENTS attributable to UTI. plausibility. Virtually all antimicro- The committee gratefully acknowl- bial agents used to treat or to pre- 6. One of the factors used to assess edges the generosity of the research- vent infections of the urinary tract the likelihood of UTI in febrile in- ers who graciously shared their data are excreted in the urine in high fants is race. Data regarding rates to permit the data set with data for concentrations. Barriers to the ef- among Hispanic individuals are lim- 1091 infants aged 2 to 24 months ac- fectiveness of antimicrobial pro- ited and would be useful for predic- cording to grade of VUR to be com- phylaxis are adherence to a daily tion rules. piled, that is, Drs Per Brandström, regimen, adverse effects associ- 7. This guideline is limited to the initial Jonathan Craig, Eduardo Garin, Gio- ated with the various agents, and management of the first UTI in febrile vanni Montini, Marco Pennesi, and the potential for emergence of anti- infants 2 to 24 months of age. Some of Gwenaelle Roussey-Kesler. REFERENCES 1. Winter AL, Hardy BE, Alton DJ, Arbus GS, 3. American Academy of Pediatrics, Commit- 4. Finnell SM, Carroll AE, Downs SM, et al. Technical Churchill BM. Acquired renal scars in chil- tee on Quality Improvement, Subcommittee report: diagnosis and management of an initial dren. J Urol. 1983;129(6):1190 –1194 on Urinary Tract Infection. Practice urinary tract infection in febrile infants and 2. Smellie JM, Poulton A, Prescod NP. Retro- parameter: the diagnosis, treatment, and young children. Pediatrics. 2011;128(3):e749 spective study of children with renal scar- evaluation of the initial urinary tract infec- 5. American Academy of Pediatrics, Steering ring associated with reflux and urinary in- tion in febrile infants and young children. Committee on Quality Improvement and fection. BMJ. 1994;308(6938):1193–1196 Pediatrics. 1999;103(4):843– 852 Management. Classifying recommenda- PEDIATRICS Volume 128, Number 3, September 2011 607 Downloaded from pediatrics.aappublications.org by guest on January 2, 2012