Acta Pædiatrica ISSN 0803–5253
REVIEW ARTICLE
Febrile urinary tract infections in young children: recommendations for the
diagnosis, treatment and follow-up
Anita Ammenti1, Luigi Cataldi2, Roberto Chimenz3, Vassilios Fanos4, Angela La Manna5, Giuseppina Marra6, Marco Materassi7, Paolo Pecile8,
Marco Pennesi9, Lorena Pisanello10, Felice Sica11, Antonella Toffolo12, Giovanni Montini ([email protected]) (Coordinator)13 on behalf
of the Italian Society of Pediatric Nephrology
1.Department of Pediatrics, University of Parma, Parma, Italy
2.Division of Neonatology, Catholic University Sacro Cuore, Roma, Italy
3.Pediatric Nephrology and Dialysis Unit, Department of Pediatrics, G. Martino Hospital, University of Messina, Messina, Italy
4.NICU and Puericulture Department, University of Cagliari, Cagliari, Italy
5.Department of Pediatrics, Second University of Napoli, Napoli, Italy
6.Pediatric Nephrology Unit, Fondazione Ca’ Granda IRCCS, Milano, Italy
7.Pediatric Nephrology Unit, Meyer Hospital, Firenze, Italy
8.Pediatric Department, University Hospital, Udine, Italy
9.Department of Pediatrics, Institute for Child and Maternal Health, IRCCS Burlo Garofolo, Trieste, Italy
10.Family Pediatrician, Padova, Italy
11.Pediatric Unit, Ospedali Riuniti, Foggia, Italy
12.Pediatric Unit, Hospital of Oderzo, Oderzo, Italy
13.Pediatric Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero-Universitaria Sant’Orsola-Malpighi, Bologna, Italy
Keywords
Antibiotic treatment, Diagnosis, Febrile urinary tract
infection, Prophylaxis, Vesico-ureteral reflux
Correspondence
Giovanni Montini, M.D., Nephrology, Dialysis Unit,
Department of Pediatrics, Azienda Ospedaliera
Universitaria Sant’Orsola-Malpighi Bologna, Via
Massarenti 11, Padiglione 13, 40138 Bologna, Italy.
Tel: +390516364617 |
Fax: +390512086000 |
E-mail: [email protected]
ABSTRACT
We report the recommendations for the diagnosis, treatment, imaging evaluation and use
of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged
2 months to 3 years. They were prepared by a working group of the Italian Society of
Pediatric Nephrology after careful review of the available literature and a consensus
decision, when clear evidence was not available.
Conclusion: These recommendations are endorsed by the Italian Society of
Pediatric Nephrology. They can also be a tool of comparison with other existing guidelines
in issues in which much controversy still exists.
Received
19 July 2011; revised 12 October 2011;
accepted 24 November 2011.
DOI:10.1111/j.1651-2227.2011.02549.x
INTRODUCTION
The recommendations suggested in this study represent the
view point of the Italian Society of Pediatric Nephrology,
which endorsed the document. They were developed by a
working group of paediatricians and paediatric nephrologists, after careful review of the available literature and a
consensus decision, when clear evidence was not available.
The recommendations apply to infants and young children, 2 months to 3 years of age, with the first febrile
(‡38C) urinary tract infection (UTI). We excluded neonates because of the peculiarities and specific treatment
needs and children older than 3 years of age because of the
lower risk of nephro-urologic abnormalities and different
clinical presentations. Children with immunodeficiency,
with a previous workup for congenital malformation of the
kidney or urinary tract or requiring admission to intensive
care unit are excluded. The recommendations are intended
for use by all physicians dealing with febrile UTIs in children inside and outside the hospital and by specialists in
paediatric and adult nephrology and urology.
Grade of evidence was attributed according to the SORT
criteria (1), to provide the physician with a clear recommendation that is strong [A], moderate [B] or weak [C] in support of a particular intervention. Four major topics are
Key notes
•
•
•
ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2012 101, pp. 451–457
Diagnosis of urinary tract infection (UTI) requires analysis of urine by dipstick or microscopy and urine culture.
Clean voided midstream collection is recommended.
Oral antibiotic treatment is recommended when the
febrile child is in good general conditions. Cephalosporins or amoxicillin–clavulanate are the suggested
antibiotics.
Ultrasound is always recommended after the first febrile
UTI, while cystography only in the presence of risk factors or anomalies on ultrasound. Antibiotic prophylaxis
is recommended for children with reflux grade ‡III.
451
Urinary tract infections in young children
Ammenti et al.
considered: diagnosis, treatment, imaging and antibiotic
prophylaxis.
DIAGNOSIS
When to suspect a urinary tract infection?
Urinary tract infection should be considered on the basis of
clinical criteria, the age and sex of the child. Fever may be
the only symptom, especially in younger children (2,3)
[grade A]. The prevalence in children <2 years of age, with
unexplained fever, is 5% (4). Fever >39C is considered a
clinical marker of renal parenchymal involvement (2).
Uncircumcised boys are more frequently affected than girls
during the first 6 months of life; thereafter, the opposite is
true (5). Symptoms may include vomiting, failure to thrive,
irritability, crying on micturition, dysuria, urgency and
abdominal pain and may vary with the age of the child.
What to do when a urinary tract infection is suspected?
Urine should be collected and analysed by dipstick or
microscopy to identify children in whom UTI is very likely
(6) and by urine culture to make a definitive diagnosis (2)
[grade B]. How to collect urine for culture has been extensively analysed by the NICE working group (7) and by
Whiting et al. (8). Suprapubic aspiration (SPA) and transurethral bladder catheterization are least likely to yield a
contaminated growth result, but these methods are not feasible as a routine procedure in primary care, at least in Italy.
Clean voided urine (CVU) has accuracy similar to SPA for
the diagnosis of UTI (8). We therefore consider CVU as the
method of choice [grade B]. When it is correctly performed
(9,10), bag-collected specimen is considered acceptable as
the second option (8,11) [grade C].
In the clinical setting, the method for urine collection varies according to the child’s clinical conditions:
Febrile child in poor general condition or severely illappearing:
Urine should be collected by transurethral bladder catheterization (3,7) [grade A]
Febrile child in good general condition:
Clean voided urine represents the method of choice. If
unsuccessful, a bag applied to the perineum is an
acceptable alternative. The bag-collected specimen
can be utilized to perform a dipstick test or microscopy, and a midstream sample can then be collected
for urine culture (3) [grade B].
What is the role of urine dipstick, microscopy and urine
culture?
Sensitivity and specificity of the components of urinalysis
(dipstick and microscopy) are well summarized in a recent
metanalysis (6) and are reported in Table 1.
Results of the leucocyte esterase test are comparable to
those of WBC (5 ⁄ hpf) by microscopy; microscopy for bacteria with Gram stain is the single rapid test with the highest
specificity and sensitivity. The diagnostic performance of
452
Table 1 Sensitivity and specificity of urinary dipstick (leucocyte esterase and nitrite)
and microscopy (WBC and bacteria) for diagnosis of urinary tract infection [adapted
with permission from Williams GJ (6)]
Test
Leucocyte esterase
Nitrite
Leucocyte esterase or nitrite positive
Both leucocyte esterase and nitrite
positive
Microscopy: WBCs
Microscopy: unstained bacteria
Microscopy: Gram stain
Sensitivity %
(range)
Specificity %
(range)
79 (73–84)
49 (41–57)
88 (82–91)
45 (30–61)
87 (80–92)
98 (96–99)
79 (69–87)
98 (96–99)
74 (67–80)
88 (75–94)
91 (80–96)
86 (82–90)
92 (83–96)
96 (92–98)
dipstick testing has been reported significantly less reliable
in children younger than 2 years (12); therefore, in this case,
urine microscopy for bacteria is recommended [grade B]. If
fever persists in children with a normal previous urinalysis
and no antibiotic treatment, a second test (dipstick or
microscopy) is recommended after 24–48 h [grade C].
Urine microscopy should be performed on a fresh specimen [grade B] by an expert operator. Urine culture is
required to confirm the diagnosis (6). The result is considered positive if the culture demonstrates the growth of a single organism with the following colony count [grade C]:
• Transurethral bladder catheterization: >10 000 colonyforming units (CFU) ⁄ mL (3)
• CVU: >100 000 CFU ⁄ mL (3)
• Urinary bag: >100 000 CFU ⁄ mL (3)
A practical approach, based on the result of leucocyte
esterase and nitrite dipstick analysis, is suggested in Table 2.
Are blood tests necessary if a urinary tract infection is suspected?
In the published guidelines and in the most recent literature,
C-reactive protein and WBC are not considered useful diagnostic tools to identify renal parenchymal involvement
because of a low specificity (13) [grade B]. In febrile children with good general conditions, blood tests are not necessary. In severely ill children, procalcitonin is considered
the best test to diagnose the presence of a renal parenchymal involvement (13,14).
TREATMENT
In a febrile child with suggestive clinical signs, positive urine
microscopy and ⁄ or dipstick, antibiotic treatment has to be
initiated after a urine specimen for culture has been
obtained. Prompt antibiotic treatment is necessary to eradicate the infection, to prevent bacteraemia (in particular,
during the first months of life), to improve the clinical condition and possibly to reduce the risk of renal scarring.
Recent data do not support the reduction in renal scarring
as no difference in the frequency and severity of scarring
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Ammenti et al.
Urinary tract infections in young children
Table 2 Interpretation and suggested practical approach following the result of nitrite and leucocyte esterase urine dipstick
Nitrite positive
UTI very likely
Perform urine culture and start antibiotic on an empiric basis
Leucocyte esterase positive
Nitrite positive
UTI very likely
Perform urine culture and start antibiotic on an empiric basis
Leucocyte esterase negative
Nitrite negative
UTI likely
Perform urine culture and start antibiotic on an empiric basis
Leucocyte esterase positive
Nitrite negative
UTI quite unlikely
Search for alternative diagnosis
Leucocyte esterase negative
Repeat urine dipstick if fever persists
UTI, urinary tract infection.
was found when antibiotic was initiated within 4 days from
the onset of fever (15). The consequences of longer delays
are unknown.
How to treat?
If the UTI is complicated, i.e. when the child appears toxic
or severely dehydrated or is vomiting, or if there are concerns regarding compliance, treatment should be started
parenterally and continued with an oral antibiotic after 2–
4 days (2) [grade A]. If the UTI is not complicated, i.e. when
the febrile child is in good clinical conditions, only slightly
dehydrated but able to retain oral fluids and medications
and a good compliance is expected, treatment should be
given by the oral route [grade A]. The results of the oral versus parenteral route do not differ regarding duration of
fever, recurrence of UTI and incidence of scars 6–
12 months after infection (16,17) [grade A]. While awaiting
the results of antimicrobial sensitivity testing, antibiotic
treatment has to be chosen on an empiric basis, ideally with
the help of local resistance patterns. As a result of increasing
resistance of Escherichia coli to amoxicillin, amoxicillin–
clavulanic acid or cephalosporin are among the most widely
utilized oral drugs (2,3,7,16–20). If the oral route cannot be
used, cefotaxime, ceftriaxone or an aminoglycoside in children allergic to beta-lactam antibiotics can be administered
Table 3 Suggested drugs and dosage for antibiotic treatment of febrile urinary tract
infection
Oral therapy
Parenteral therapy
Amoxicillin–Clavulanic acid:
50 mg ⁄ kg ⁄ day of
amoxicillin in three doses
Amoxicillin–Clavulanic acid: 100 mg ⁄ kg ⁄
day of amoxicillin in four doses by
i.v.infusion in 30 min
or
Ampicillin–Sulbactam: 100 mg ⁄ kg ⁄ day
of ampicillin in four doses by i.v.infusion
in 30 min
Cefotaxime: 150 mg ⁄ kg ⁄ day in 3–4 doses
Cephalosporins:
Cefixime: 8 mg ⁄ kg twice
daily 1st day, once
daily thereafter (16)
Ceftibuten: 9 mg ⁄ kg twice
daily 1st day, once
daily thereafter (19)
Ceftriaxone: 50–75 mg ⁄ kg once daily
Aminoglycosides (once-daily administration
recently suggested) (21,22)
parenterally for 2–4 days, followed by an oral antibiotic
course (2,17) [grade A] (Table 3).
How long to treat?
There is no consensus in the literature on the optimal duration of antimicrobial therapy (18). Studies comparing antibiotic courses of different duration in acute pyelonephritis
are lacking. 7–14 days of antimicrobial treatment is generally recommended, while a 10-day course seems reasonable
and appropriate [grade C]. However, parenteral therapy
can be limited to 3 days in most cases, followed by a 7-day
oral course, as treatment failure does not appear to be associated with the duration of intravenous antibiotic treatment
(23) [grade B].
When should a child be hospitalized?
Hospital admission is indicated in the following situations
(3) [grade C]:
•
•
•
•
Infants younger than 3 months.
Severely ill children (sepsis, dehydration and vomiting).
Concern of noncompliance.
Fever persisting after 3 days of appropriate antibiotic
treatment as shown by the sensitivity testing.
IMAGING
There is no consensus in the existing guidelines on imaging
evaluation in children following a febrile UTI. In children
younger than 2 years of age, a number of guidelines (2,3)
place importance on detecting vesico-ureteral reflux (VUR)
and therefore on the necessity to perform cystography. The
more recent NICE guidelines (7) only recommend a radiologic evaluation of the urinary tract in selected patients.
Similar opinions have been expressed by others (24,25),
who suggest the use of cystography only if US or radionuclide renal scan (RRS) demonstrates abnormalities. The use
of RRS to reveal the presence of renal parenchymal localization of the infection during the acute phase of the disease,
referred to as the top-down approach, limits cystography to
children showing pyelonephritis (26,27). A very recent
paper, examining the results of a prospective study on children with the first febrile UTI, suggests that an abnormal US
is the key for performing a cystography (28).
ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2012 101, pp. 451–457
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Urinary tract infections in young children
Ammenti et al.
Lack of consensus in imaging evaluation depends mainly
on the following reasons:
1 The poor correlation between the severity of UTI and the
presence or absence of VUR;
2 the debated role of VUR in the appearance of renal
scars;
3 the trend of VUR to the spontaneous resolution;
4 the psychological stress and radiation of imaging; and
5 the unclear yield of the tests in improving the long-term
health of the patients.
A systematic review of the literature (24) and a recent
study (29) do not fully support the existing notion that
VUR is a crucial element for renal damage following a
UTI. Another reason that casts doubts on the absolute
need for the diagnosis of VUR is the finding that chronic
kidney damage is significantly related to congenital renal
dysplasia rather than to infections and VUR (30). Other
authors (31), on the contrary, describe a pivotal role of
VUR in the formation of renal scars. In addition, the role
of prophylaxis in reducing subsequent infections and scarring is uncertain (32–37).
Therefore, there is no scientific evidence for a specific
diagnostic evaluation of children following a febrile UTI.
First febrile UTI
Urinary tract US
Abnormal
Normal
No risk factors
(hydronephrosis, ureteric dilatation, hypoplasia,
duplicated system, bladder abnormalities)
or Risk factors:
- Abnormal prenatal US
Further imaging unnecessary
- First degree relative with VUR
- Septicemia
- Chronic kidney disease
- Age < 6 month in a male infant
- Likely non-compliance of the family
2nd febrile UTI
- Abnormal bladder emptying
- No clinical response to correct antibiotic
treatment within 72 h
- Bacteria other than E. coli
Further imaging ( cystography, renal radionuclide scan)
Figure 1 Suggested imaging approach after a febrile urinary tract infection in
children aged 2 months to 3 years of age.
454
Our recommendations represent a consensus of current
opinions and are subject to change as the results of further
well-conducted prospective studies become available.
We propose a flow chart (Fig. 1) aimed at diagnosing
higher-grade reflux, with or without renal damage, and at
avoiding unnecessary evaluation and treatment, potentially
harmful for children and families.
When should an ultrasound be performed?
Renal US is an important noninvasive tool, which allows a
re-evaluation and a more detailed description of prenatally
detected abnormalities (38,39) and can identify malformations (isolated hydronephrosis, hydroureteronephrosis,
renal hypoplasia, duplicated systems and bladder abnormalities) associated with VUR in a significant percentage of
cases (40). This imaging technique needs standardization
(25), requiring examination of the longitudinal and transverse diameters, echogenicity and cortico-medullary differentiation of the kidney and measurement of anteroposterior diameter of the pelvis with full and empty bladder,
ureteric dilatation, bladder wall and postvoiding volume.
Routinely, US can be performed within 1–2 months from
the infection; in children with no clinical response to a correct antibiotic therapy within 3 days, US should be performed promptly [grade C] if renal abscess is suspected. If
US is normal and no risk factors are present, further imaging is not indicated [grade B]. If US shows abnormalities or
risk factors are present, a complete morphologic evaluation
of the kidney and urinary tract (cystography and RRS) is
indicated [grade B].
Suggested risk factors include the following (Fig. 1):
In utero or postnatal US abnormalities: hydronephrosis,
ureteral dilatation, duplicated system, renal hypoplasia,
loss of cortico-medullary differentiation or abnormal
parenchymal echogenicity, bladder wall thickening or
irregularity, postmicturating abnormal residual urine
volume and bladder diverticula (25,28) [grade B].
Family history of VUR: from a recent meta-analysis, the
prevalence of VUR is 27.4% (range 2.9–51.9) in siblings
and 35.7% (range 16.4–61) in offspring screened (41)
[grade B].
Septicaemia: UTI is associated with sepsis in about 10% of
infants. When sepsis is present, the risk of urologic
abnormalities has been reported higher (42,43) [grade
C].
Renal insufficiency (24,44) [grade A].
Male infants <6 months of age [grade C].
Suspicion of noncompliance of the family, which requires a
more stringent diagnostic approach, to avoid dropouts
and the loss to follow-up of children that could be at risk
of renal damage [grade C].
Micturition abnormalities or thickened bladder wall, which
may indicate posterior urethral valves (45) [grade B].
Absence of a clinical response to antibiotics within 72 h,
with persistence of fever [grade C].
Pathogens other than E. coli. P fimbriated E. coli bind to
uroepithelial cells and resist to the normal urine flow.
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Ammenti et al.
Nonfimbriated bacteria ascend the urinary tract with the
help of obstruction or reflux (43,46) [grade B].
When should further renal imaging be performed?
In a child with an abnormal US or the presence of one of
the previous risk factors, we suggest further imaging of the
urinary tract (cystography) and the renal parenchyma
(RRS) [grade B]. The choice of the technique for the diagnosis of VUR (cystosonography, radionuclide cystography and
voiding cystourethrography) depends on the expertise of
the local team, keeping in mind that imaging should be performed with the minimum radiating dose. The technique
having no radiating dose is cystosonography. Scientific evidence has shown that this technique has a high sensitivity
and specificity (47–49). The limits of the method could be
overcome by skilled operators who, however, are not yet
widely available (50,51) [grade B]. Radionuclide cystography, although not showing exact anatomical details and not
visualizing the urethra, has a high sensitivity also for transient low-grade VUR. Cystourethrography (VCUG) remains
the gold standard, permitting an exact grading according to
the International Working Group on VUR in children (52),
but because of its higher radiating dose, it should be limited
to selected patients (in particular, to males in whom there is
a suspicion of posterior urethral valves). The timing of cystourethrography can be established according to local organization and to family convenience, as there is evidence
that neither the presence nor the grade of VUR is influenced
by the timing of the examination following diagnosis of UTI
(53–55) [grade B].
In all children with an abnormal US or in whom VUR has
been shown, a renal cortical scintigraphy (with DMSA) is
recommended 6 months after the febrile UTI, to obtain a
morphologic (presence of UTI-related renal scarring) and
functional evaluation (relative renal function) of the renal
parenchyma [grade C].
In children with febrile UTI presenting none of the risk
factors discussed above, no further imaging of the urinary
tract and of the renal parenchyma is recommended [grade
C]. In case of recurrence of febrile UTIs, cystography and
renal DMSA scan should be performed [grade B].
ANTIBIOTIC PROPHYLAXIS
Antibiotic prophylaxis has been widely used in the past in
children following a febrile UTI, in the hypothesis that renal
damage and its progression could be avoided by preventing
recurrent UTI. The effectiveness of prophylaxis remains
uncertain. In a meta-analysis (56), comprising in particular
five recent trials (32–36), there is no evidence for a positive
effect of antibiotic prophylaxis in the prevention of recurrent febrile UTIs and kidney damage. It is important to
acknowledge that most of the evaluated studies had limitations regarding the methodological design and enrolled
children mainly with no or with reflux grade up to III. On
the contrary, in one of the largest trials (576 children) comprised in the metanalysis, the use of antibiotic prophylaxis
Urinary tract infections in young children
demonstrates a modest favourable effect on the recurrence
of both symptomatic and febrile UTIs (36). A more recent
RCT (203 children) shows favourable effects on the recurrence of infections, especially in girls >1 year old, with
reflux grades III and IV (37). There was no benefit in boys
from any of the treatments (antibiotic prophylaxis or endoscopic correction of reflux) in that study. An increased bacterial resistance to the prophylactic drug has been described
in these studies.
When antibiotic prophylaxis should be recommended?
Antibiotic prophylaxis should not be recommended routinely in infants and children after the first UTI [grade A].
It has to be considered in infants and in children:
1 after the treatment for the acute episode until cystography is performed [grade C].
2 with reflux grade ‡III [grade B].
3 with recurrent febrile UTIs [grade C] (‡3 febrile UTIs
within 12 months).
The optimal duration of antibiotic prophylaxis is not well
established; we suggest 1–2 years [grade C]. Amoxicillin–
clavulanic acid and cotrimoxazole are the most common
antibiotics utilized in the literature, but their resistance rates
are increasing.
ACKNOWLEDGEMENTS
The working group of the Italian Society of Pediatric
Nephrology is grateful to the association ‘Il Sogno di Stefano (Stefano’s Dream)’ for financial support in preparation
of these recommendations.
DISCLOSURE
All authors participated in writing the first draft of the manuscript, and no honorarium, grant or other forms of payment were given to anyone to produce the manuscript.
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