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Evaluation and management of recurrent urinary tract infections in children: state of the art Expert Rev. Anti Infect. Ther. 13(2), 209–231 (2015)
Muhammad Awais*1, Abdul Rehman2, Noor Ul-Ain Baloch2, Farid Khan3 and Naseer Khan4 1 Department of Radiology, Aga Khan University Hospital, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 2 Department of Biological and Biomedical Sciences, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 3 Department of Surgery, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 4 Department of Pediatrics, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan *Author for correspondence: Tel.: +92 300 903 4827 [email protected]
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Urinary tract infections (UTIs) represent an important cause of febrile illness in young children and can lead to renal scarring and kidney failure. However, diagnosis and treatment of recurrent UTI in children is an area of some controversy. Guidelines from the American Academy of Pediatrics, National Institute for Health and Clinical Excellence and European Society of Paediatric Radiology differ from each other in terms of the diagnostic algorithm to be followed. Treatment of vesicoureteral reflux and antibiotic prophylaxis for prevention of recurrent UTI are also areas of considerable debate. In this review, we collate and appraise recently published literature in order to formulate evidence-based guidance for the diagnosis and treatment of recurrent UTI in children. KEYWORDS: antibiotic prophylaxis . cystitis . pyelonephritis . urinary tract anomalies . urinary tract infection .
vesicoureteral reflux
Urinary tract infection (UTI) is an important cause of febrile illness among young children throughout the world. It has been estimated that by the age of 6 years, 2% of boys and 7% of girls would have experienced at least one symptomatic UTI [1]. A meta-analysis of 14 prevalence studies, published in 2008, observed that the prevalence of UTI among febrile children was highest in uncircumcised boys under the age of 3 months (pooled prevalence of 20.1%) and girls aged 6–12 months (pooled prevalence of 8.3%) [2]. Even among older children (5 years) may report specific urinary complaints, such as frequency, burning micturition and offensive urine. UTI may also present in toilet-trained children as new-onset urinary incontinence or bed-wetting. However, several studies published in the past few decades have also recognized UTI as an important cause of febrile illness in children [24]. This finding underscores the importance of considering UTI in the differential diagnosis of any child presenting with fever. Laboratory testing of urine specimens is both useful and essential for making a diagnosis of UTI. Three different types of tests are commonly performed on urine specimens – urine dipstick, microscopy and culture. Urine dipstick, which is often performed at the patient’s bedside, can indicate the presence of leukocyte esterase and nitrite. Sensitivity and specificity of leukocyte esterase alone have been reported to be approximately 79 and 87%, respectively, while these values for nitrite alone are around 49 and 98%, respectively [25]. When the two tests are used together, sensitivity increases to 87%, while specificity goes down to 79% [25–27]. Urine microscopy allows direct visualization of leukocytes and bacteria in the urine. In most laboratories, urine dipstick and microscopy are performed and reported together (‘urinalysis’). This urinalysis confers a higher sensitivity of 99.8% with a specificity of 70% [19,25]. Urine culture not only detects the presence of bacteria in the urine but also provides information about the sensitivity patterns. However, a prerequisite for urine culture and sensitivity is an uncontaminated sample of urine. While a clean-catch, midstream sample of urine can be obtained satisfactorily in older children, this is not possible in infants and younger children. For such children, catheterization can provide an uncontaminated sample of urine for culture. However, in certain cases (labial adhesions, phimosis), even catheterization may not be possible; suprapubic aspiration of bladder can provide a clean sample of urine for culture in such patients. High-quality evidence has shown that culture of urine obtained by catheterization has a sensitivity and specificity of 95 and 99%, respectively, which are comparable to those obtained by suprapubic aspiration [28,29]. For a diagnosis of UTI, quantification of bacterial growth on urine culture is important. This is because voided urine specimens can be contaminated by distal urethral and perineal flora. For clean-catch, midstream urine samples, growth of ‡100,000 CFU/ml of a known uropathogen suggests UTI or asymptomatic bacteriuria. When a urine specimen has been obtained by catheterization, growth of ‡10,000 CFU/ml of a pathogenic bacterium is also considered significant. In samples obtained by suprapubic aspiration, even growth of a single organism is considered abnormal [1,23,30]. informahealthcare.com
Review
4514 articles identified by initial search
756 duplicate entries
1673 deemed irrelevant
2085 abstracts reviewed
820 focused on adults
126 focused on first UTI
1139 full-text retrieved 23 additional articles identified through reference lists 57 focused on irrelevant aspects
1105 articles included
SR/MA Clinical trials Observational studies Secondary literature
22 33 408 642
Figure 1. A flow chart depicting the inclusion and exclusion of articles for the purpose of this review. MA: Meta-analyses; SR: Systematic reviews; UTI: Urinary tract infection.
In clinical practice, urinalysis and urine culture are used together in conjunction with the patient’s clinical features to make a diagnosis of UTI. Urinalysis is warranted in all children who present with clinical features suggestive of a UTI [22]. Evidence supports routinely obtaining urinalysis in febrile children with no apparent source of infection [31]. In febrile children for whom empiric antibiotic therapy has to be instituted, urinalysis along with urine culture and sensitivity should be obtained prior to the start of antimicrobial therapy. Urine culture should also be obtained in children with a positive urinalysis before starting antimicrobial treatment [16,19]. While examination of urine specimens can provide evidence of a UTI, such investigations cannot differentiate between infections of the lower (cystitis) and upper (pyelonephritis) urinary tract. Studies have shown that the presence of high-grade fever or severe illness is highly predictive of pyelonephritis. Furthermore, pyelonephritis is also suggested by the presence of flank pain or tenderness [16,32]. Definitive diagnosis of 211
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pyelonephritis can be made with the help of radionuclide imaging of the kidneys [33]. However, differentiation between upper and lower UTI often does not alter the immediate management of a patient. Therefore, routine use of diagnostic imaging for localization of UTI is not justified [34].
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Etiology of UTI
While adenovirus and Candida spp. can cause UTI in children, the vast majority of UTI in children are due to bacterial pathogens [23]. The most common bacterial pathogens isolated are gram-negative rods (E. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas spp.) and gram-positive cocci (Streptococcus agalactiae, Enterococcus spp.) [35]. Some studies have demonstrated sex- and age-specific trends. E. coli more commonly infects neonatal boys than girls [36]. Likewise, uncircumcised boys are more prone to develop UTI due to Proteus spp., while Staphylococcus spp. frequently infect adolescent girls [37,38]. The role of certain host (uropathogenic colonic flora, perimeatal colonization in uncircumcised boys, short urethra in girls, LUTD, VUR) and bacterial (lipopolysaccharide, K capsular antigen, hemolysin, aerobactin, p-fimbriae) virulence factors in the pathogenesis of UTI is well established [10,39]. Recent research has shown that innate immunity and urinary tract responses also play a crucial role in the development of UTI [9]. Genetic polymorphisms in the genes for HSPA1B, TLR4, CXCR1, CXCR2, IL-8 and IL-10 have been shown to predispose patients to the development of UTI [40–42]. New virulence characteristics, such as the formation of biofilms and intracellular bacterial communities, have been identified that allow the persistence of uropathogenic bacteria and recurrence of UTI [43,44]. Resistance of uropathogenic organisms to traditional antibiotics is increasing over time and this poses a major public health concern for both developed and developing countries [45]. A meta-analysis of antimicrobial resistance among neonatal pathogens in developing countries reported that resistance of E. coli to ampicillin and trimethoprim–sulfamethoxazole (TMP–SMX) was 72 and 78%, respectively. Similarly, resistance of Klebsiella spp. to gentamicin and third-generation cephalosporins was 60 and 66%, respectively [46]. Routine antibiotic prophylaxis with TMP-SMX may also increase the prevalence of TMP-SMX-resistant organisms [21,47,48]. In vitro studies have shown that in children prescribed TMP–SMX for longterm prophylaxis, E. coli strains tend to rapidly acquire antibiotic resistance genes [49]. Treatment of active UTI
Prompt recognition and treatment of UTI is essential and evidence has shown that delaying treatment in young children with UTI while awaiting results of laboratory investigations is harmful [30]. Children who have clinical features highly suggestive of UTI and positive urine dipstick and/or microscopy should be started on empiric antibiotic therapy. Furthermore, in children with high-grade fever or signs of severe illness, empiric antibiotic treatment should be started after sending urine for urinalysis and culture [16,19,24]. 212
Choice of antibiotics for empiric treatment of patients with suspected UTI should be based on local data of antibiotic susceptibility. Empiric antimicrobial agents should have appropriate activity against gram-negative rods and gram-positive cocci [35]. The empiric agent should be switched to an appropriate antimicrobial agent depending on the results of urine culture and sensitivity. In the past, amoxicillin and TMP–SMX were used as empiric antibiotics. However, due to increasing resistance to these drugs, many pediatricians now prefer to use cephalosporins (cephalexin, cefpodoxime and cefixime) or amoxicillin–clavulanate as empiric agents [45,46]. Dosage of common antimicrobial agents is summarized in TABLE 1. Traditionally, children diagnosed to have cystitis were treated orally, while those with acute pyelonephritis were started on intravenous antibiotics. However, several studies have shown that treatment of UTI (both cystitis and acute pyelonephritis) with oral antibiotics is as safe and effective as parenteral therapy [50–53]. In a clinical trial by Bocquet et al., there was no difference in resolution of fever or presence of renal scar at 6 months among those treated with intravenous ceftriaxone plus oral cefixime versus those treated with oral cefixime alone [54]. In another multicenter randomized clinical trial, Hoberman et al. found no significant difference in the incidence of recurrent UTI among children treated with oral antibiotics alone versus those treated initially with intravenous antibiotics [55]. Parenteral antimicrobial therapy may be appropriate for children who are unable to tolerate orally or appear systemically unwell. Third-generation cephalosporins or a combination of ampicillin and gentamicin are the commonly used intravenous antibiotics [16,19]. Duration of therapy for UTI has also been validated by some studies. Some evidence suggests that single-day antibiotic regimens are harmful in children with UTI [56]. Three-day regimens of TMP–SMX or nitrofurantoin are acceptable for older (>3 years) children with typical features of uncomplicated cystitis [57]. Many studies have also shown that outcome of children with pyelonephritis treated with a short (3–4 days) course of antibiotics versus those treated with a longer (7–10 days) course of antibiotics is similar [51,52,58,59]. Recommendations of treating younger (3 years) children with complicated UTI or pyelonephritis with a 10-day course of antibiotics are based on expert advice [16,19]. It has also been suggested that antimicrobials which achieve therapeutic concentrations only in the urine, such as nitrofurantoin, should not be used to treat pyelonephritis [19]. This is based on the presumption that serum antimicrobial concentrations are not sufficient to prevent the development of urosepsis and septic shock. Diagnostic imaging modalities
Diagnostic imaging for children with recurrent UTI is a constantly evolving field and no single diagnostic algorithm is agreed upon by all. Different approaches have been proposed for imaging young children with recurrent UTI. However, certain key principles are common to all these approaches, as explained below. Expert Rev. Anti Infect. Ther. 13(2), (2015)
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Table 1. Common antibiotics used for the treatment of urinary tract infections. Antibiotic
Class of agent
Route
Dosage
Adverse effects
Amoxicillin
Penicillin
Oral
40 mg/kg/day in three divided doses
Ampicillin
Parenteral
100 mg/kg/day in four divided doses
Allergy, rash, GI disturbance, pseudomembranous colitis
Amoxicillin–clavulanate
Oral, parenteral
40 mg/kg/day of amoxicillin in three divided doses
Piperacillin
Parenteral
200–300 mg/kg/day in four divided doses
Oral
50 mg/kg/day in three to four divided doses
Cefixime
Oral
8 mg/kg/day in one to two divided doses
Cefotaxime
Parenteral
100–200 mg/kg/day in three to four divided doses
Ceftazidime
Parenteral
100–150 mg/kg/day in three divided doses
Ceftriaxone
Parenteral
50–75 mg/kg/day
Cefpodoxime
Oral
10 mg/kg/day in two divided doses
Parenteral
7.5 mg/kg/day in three divided doses
Parenteral
15 mg/kg/day in one to three divided doses
Oral
6–12 mg/kg/day of trimethoprim in two divided doses
Cephalexin
Gentamicin
Cephalosporin
Aminoglycoside
Amikacin Trimethoprim– sulfamethoxazole
Sulfonamide
Allergy, rash, GI distress, pseudomembranous colitis, cholestasis†
Nephrotoxicity, ototoxicity
Steven–Johnson syndrome, myelosuppression, hepatotoxicity
† Cholestasis frequently occurs in neonates treated with ceftriaxone. GI: Gastrointestinal.
The ‘bottom-up’ approach was conventionally used in the past for evaluation of children with UTI. This approach was based on the proposition that children with VUR are more prone to develop pyelonephritis, and therefore, children presenting with a UTI must be evaluated for the presence of VUR [60]. Voiding cystourethrography (VCUG) was routinely performed in children who had experienced a febrile UTI [61]. This contrast-enhanced fluoroscopic study was not only invasive but also exposed young children to a significant radiation dose [62]. Identification of VUR in children would prompt imaging of the kidneys to detect the presence of renal scarring and institution of antibiotic prophylaxis or surgery to treat VUR. In this approach, emphasis was on the detection of VUR that would provide the opportunity to prevent further renal damage. The ‘bottom-up’ approach was not supported by evidence accumulated over the past several decades. Studies showed that many children developed pyelonephritis and renal scars, even in the absence of VUR [63,64]. Furthermore, many studies suggested that prompt recognition and treatment of children with pyelonephritis was better than subjecting all children with VUR to antibiotic prophylaxis and/or surgery [65–68]. It was also observed that many children with VUR improved over
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time and did not develop pyelonephritis [69,70]. While VCUG was sufficiently accurate in the detection of VUR, yield of VCUG in the ‘bottom-up’ approach was quite low (~1%) and this entailed unnecessary radiation exposure and discomfort for a significant proportion of children [19,71]. Consequently, in the light of new evidence, a ‘top-down’ approach to diagnostic imaging was adopted. The ‘top-down’ approach for diagnostic imaging shifted the focus from identification of children with VUR to identification of children at risk of developing renal scars (FIGURE 2). Studies reported from the USA demonstrated that third-trimester antenatal ultrasonography was effective in detecting most clinically significant urinary tract anomalies [72,73]. Therefore, in children with documented normal antenatal imaging, clinically significant urinary tract abnormalities are unlikely, even in the presence of UTI [74,75]. However, fetuses identified to have antenatal hydronephrosis require ultrasonography after birth along with radionuclide renal scanning and/or VCUG [17]. As for children who develop UTI, guidelines differ in the indications for various imaging modalities and the exact protocol to be followed (BOX 2). Guidelines developed by the American Academy of Pediatrics, National Institute for Health and Clinical Excellence and
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Awais, Rehman, Baloch, Khan & Khan
Febrile UTI
Bottom-up approach
Continue follow-up
DMSA scan
Renal scars noted
Normal
Renal scarring
Normal
Consider antibiotic prophylaxis
Consider antibiotic prophylaxis VCUG
Top-down approach
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Normal
Abnormal
Consider surgical or endoscopic intervention
DMSA scan
U/S
VUR < grade IV
VUR present Febrile UTI
VCUG
VUR absent
Continue follow-up
VUR grade IV–V Consider surgical or endoscopic intervention
Figure 2. A comparison of the ‘bottom-up’ and ‘top-down’ approaches of diagnostic imaging. DMSA: Dimercaptosuccinic acid; U/S: Ultrasonography; UTI: Urinary tract infection; VCUG: Voiding cystourethrography; VUR: Vesicoureteral reflux.
European Society of Paediatric Radiology are based on some common considerations about various diagnostic imaging modalities. Imaging of the kidneys by ultrasonography and/or renal scintigraphy can be performed either during the febrile illness (to diagnose pyelonephritis) or several months later (to detect renal scars). Ultrasonography is known to have a low accuracy for predicting VUR or even pyelonephritis [76,77]. However, in children with normal antenatal imaging, performing an ultrasound will help to identify only those children who have clinically significant hydronephrosis or scarring. Children with mild and clinically insignificant VUR may be missed in such an approach; however, VUR in such children is usually inconsequential and, in most cases, will resolve with age [78]. Dimercaptosuccinic acid (DMSA) renal scintigraphy has been shown to be the most accurate imaging modality for detecting pyelonephritis and renal scarring [79]. DMSA, during acute illness, is generally reserved for children with an abnormal ultrasound, or those with a normal ultrasound and a high clinical suspicion of pyelonephritis [16,17]. On the other hand, DMSA is routinely used in young children with recurrent UTI to assess renal function and quantify renal scarring [80]. Although DMSA entails exposure to radiation, the dose is much lower compared to VCUG [81]. In the ‘top-down’ approach, VCUG is reserved only for patients who have abnormal ultrasonography and evidence of renal damage on DMSA scans. This approach confers excellent accuracy for detecting high-grade VUR (TABLE 2) [33,82–88]. Moreover, it obviates the need of VCUG in almost 50% of children, who
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would otherwise be subjected to VCUG in a ‘bottom-up’ approach. Newer imaging modalities are currently being investigated in order to develop a modality that would non-invasively diagnose VUR. Contrast-enhanced voiding urosonography has shown some promise for the detection of VUR in young girls [89]. However, this technique is time consuming, operator dependent and not widely available [90]. Radionuclide cystography has been proposed as an alternative to VCUG for the detection of VUR with an acceptable accuracy and radiation dose [91]. More recently, magnetic resonance urography has been employed for the detection of renal scarring in children with recurrent UTI [92]. MR–VCUG may be equivalent to conventional VCUG in detecting VUR without the associated radiation hazard [93]. More evidence is needed before these newer imaging modalities can be recommended for routine use in clinical practice. Another area that merits attention is screening of siblings of children diagnosed to have VUR. Studies have shown that VUR tends to run in families and screening of siblings can allow detection of asymptomatic VUR at earlier grades [94,95]. Furthermore, VUR detected in siblings after a UTI is often high grade and associated with renal scarring [96]. Some studies have also reported the presence of high-grade VUR and renal scarring in asymptomatic siblings [97]. While these studies suggest that screening of siblings should be performed, there is insufficient evidence to support a single diagnostic algorithm [98]. Expert advice is to obtain renal ultrasonography
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Box 2. Diagnostic imaging algorithms recommended by the National Institute of Health and Clinical Excellence, the European Society of Paediatric Radiology and the American Academy of Pediatrics. NICE . .
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.
. .
Routine imaging for children with a first UTI is not recommended Ultrasound during the acute phase should only be performed in cases of an ‘atypical UTI’ (septicemia, raised serum creatinine, abdominal mass, failure to respond to treatment within 48 h, infection with an organism other than Escherichia coli, poor urine flow or seriously ill child) Ultrasound after 6 weeks may be performed for children with recurrent UTI (defined as ‡2 episodes of pyelonephritis, or ‡3 episodes of cystitis, or 1 episode of pyelonephritis along with ‡1 episode of cystitis) or for those with a first UTI below the age of 3 months DMSA scan should be performed in children with atypical or recurrent UTI 4–6 months after the acute infection VCUG is to be performed only in those children who are under the age of 3 months and have experienced atypical or recurrent UTI
AAP . . . .
Children of age 2–24 months should routinely undergo renal and bladder ultrasonography during a febrile UTI If ultrasonography reveals hydronephrosis, scarring or any other signs of obstructive uropathy, VCUG should be performed VCUG should also be performed in other atypical or complex clinical situations Children who experience recurrence of a febrile UTI should be evaluated further
ESPR .
.
. .
.
. .
Routine imaging is not recommended for children with a UTI who have documented, normal, antenatal (third-trimester) ultrasonography and not have atypical clinical features Ultrasound with amplitude-coded color Doppler should be performed during the acute phase for children less than 1 year of age or those older than 1 year of age with serious illness Children with a normal ultrasound do not need further follow-up In cases where ultrasound is equivocal and clinical suspicion of pyelonephritis is high, acute-phase DMSA scan should be performed Children with evidence of pyelonephritis on DMSA scan or ultrasonography require: follow-up ultrasound after resolution of UTI; DMSA scan after 6–12 months; and evaluation for VUR if less than 1 year of age, or 1–5 years of age with abnormal follow-up ultrasonography, or greater than 5 years of age with recurrent UTI Evaluation of VUR should be performed by VCUG in boys and ce-VUS in girls (if available) Follow-up of VUR should be performed by RNC or ce-VUS
AAP: American Academy of Pediatrics; ce-VUS: Contrast-enhanced voiding urosonography; DMSA: Dimercaptosuccinic acid; ESPR: European Society of Paediatric Radiology; NICE: National Institute of Health and Clinical Excellence; RNC: Radionuclide cystography; UTI: Urinary tract infection; VCUG: Voiding cystourethrography; VUR: Vesicoureteral reflux.
along with DMSA scintigraphy to detect renal injury or scarring [99]. Routine VCUG for screening siblings is not recommended; VCUG should only be performed in siblings found to have significant renal scarring and/or compromised renal functions on DMSA scintigraphy [18,20]. European Society of Paediatric Radiology has also included contrast-enhanced voiding urosonography as a non-invasive screening modality for siblings of children diagnosed with VUR [17]. Antimicrobial prophylaxis
One of the rather controversial areas in the management of recurrent UTI is antimicrobial prophylaxis. Initially, when the association between pyelonephritis and VUR was recognized, treatment for VUR was thought to prevent renal scarring and its associated long-term complications [100]. Antimicrobial prophylaxis was proposed as a method to prevent recurrent UTI and subsequent renal damage. Surgery was performed for patients who had persistent VUR or developed UTI despite
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antimicrobial prophylaxis. This strategy was thought to prevent the development of renal scars, thereby reducing the incidence of hypertension, pre-eclampsia and end-stage renal disease [101]. Several studies published over the last two decades have challenged this notion [65,102]. Many studies have demonstrated that pyelonephritis can develop even in the absence of VUR [63,64]. Earlier studies, which reported a high prevalence of renal scars among children with recurrent UTI, were performed at a time when antenatal imaging was not widely available [103]. With the implementation of routine third-trimester ultrasonography, most congenital renal abnormalities (including antenatal hydronephrosis) began to be detected before the development of a UTI [72–75]. Prospective studies performed in children without any urinary tract malformations (other than VUR) failed to reveal any association between the development of pyelonephritis and subsequent renal dysfunction [104,105]. These studies suggested that pyelonephritis often resulted in the formation of small cortical scars, which were inconsequential in the long 215
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Table 2. Accuracy of ultrasonography vis-a`-vis dimercaptosuccinic acid scan for predicting high-grade (III–V) vesicoureteral reflux on voiding cystourethrography. Study (year)
Diagnostic modality
Sensitivity (%)
Specificity (%)
Awais et al. (2014)
Ultrasonography
100
18
DMSA scan
95.45
35.71
Both modalities abnormal
95.45
60.71
Either modality abnormal
100
17.86
Ultrasonography
83.33
61.18
DMSA scan
83.33
68.64
Both modalities abnormal
72.92
81.49
Either modality abnormal
93.75
48.33
Mantadakis et al. (2011)
DMSA scan
71
67
[33]
Fouzas et al. (2010)
DMSA scan
76
63.5
[84]
Lee et al. (2009)
Ultrasonography
67.2
46.2
[85]
DMSA scan
65.5
63.8
Either modality abnormal
83.2
38.6
Preda et al. (2007)
DMSA scan
96
57.6
[86]
Tseng et al. (2007)
DMSA scan
100
34
[87]
Hansson et al. (2004)
DMSA scan
80.55
80.9
[88]
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Quirino et al. (2011)
Ref. [82]
[83]
DMSA: Dimercaptosuccinic acid.
run [9]. Studies performed in adolescents with chronic renal failure also observed that recurrent pyelonephritis was not a leading cause of end-stage renal disease [106]. In the light of these studies, the actual benefit of antimicrobial prophylaxis for children with VUR became questionable. Several randomized controlled trials were completed between the years 2006 and 2014. Results of four randomized controlled trials failed to show any benefit of antimicrobial prophylaxis [107–109]. On the other hand, three randomized controlled trials were able to demonstrate statistically significant, but clinically modest, benefit from TMP–SMX prophylaxis (TABLE 3) [21,47,110]. Three different meta-analyses and/ or systematic reviews were published during the same period and gave conflicting conclusions (TABLE 4) [111–114]. The most recent systematic review by Williams and Craig reported that antimicrobial prophylaxis likely provided a modest reduction in the frequency of recurrent UTI [111]. However, this conclusion was based on the results of only two randomized controlled trials, of which one did not report any statistically significant benefit of antimicrobial prophylaxis [47,107]. Williams and Craig argued that pooled results inclusive of other randomized trials provided imprecise point estimates with marked heterogeneity [111]. Consistent with their observation, the largest (and also the most recent) randomized study, the RIVUR trial, showed a modest reduction in recurrence of UTI in children administered TMP–SMX prophylaxis (BOX 3) [21]. (It is noteworthy that this study had not been completed when the systematic review
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by Williams and Craig was published in 2011.) A meta-analysis of all seven trials shows a definitive benefit of prophylactic antibiotics (FIGURE 3). However, even the RIVUR study failed to show a significant difference in the incidence of renal scars among children who received placebo versus those who received TMP–SMX. While some reduction in the frequency of recurrent UTI may be achieved with TMP–SMX prophylaxis, this benefit has to be weighed against the potential harms associated with antimicrobial prophylaxis. There were fewer side effects associated with TMP–SMX prophylaxis in most randomized trials [21,47,107]. However, this risk of adverse effects should be considered in conjunction with the need to administer 16 patientyears of TMP–SMX to prevent a single UTI (as inferred from the RIVUR study) [21]. Another concern is the increase in antibiotic-resistant virulent organisms, which may potentially lead to serious infections [115]. In most randomized trials, children receiving antibiotic prophylaxis were more prone to develop infections due to resistant organisms [21,47,107]. Some studies suggest that oral administration of prophylactic antibiotics can change the pattern of enteric flora favoring a preponderance of antibiotic-resistant bacteria [116]. Such organisms may potentially cause serious infections in close family members of the patient. While these concerns do seem valid, large-scale studies of children followed for several (15–20) years would be needed to quantify the harm resulting from antimicrobial prophylaxis vis-a`-vis the benefit obtained [117]. In the absence of
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[214]
0.68–2.11
>0.05 RR: 1.233 100 (50 vs 50) None TMP–SMX versus no treatment
Studies published before the year 2005 are not tabulated here. HR: Hazard ratio; PRIVENT: Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteral Reflux and Normal Renal Tracts; RIVUR: Randomized Intervention for Children with Vesicoureteral Reflux; RR: Relative risk; TMP–SMX: Trimethoprim–sulfamethoxazole; UTI: Urinary tract infection; VUR: Vesicoureteral reflux.
Pennesi et al. (2006)
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†
[109]
0.9 and 0.06 for the two groups Rate of UTI in children with VUR: 22.4 versus 23.3%; rate of UTI in children without VUR: 8.8 versus 23.6% VUR (treatment vs none) and no VUR (treatment vs none) Garin et al. (2006)
None
218 (55 vs 58 and 45 vs 60)
[108]
>0.05 TMP–SMX versus no treatment Roussey-Kesler et al. (2008)
None
Not reported UTI occurred in 18/ 103 versus 32/122 225 (103 vs 122)
[107]
TMP–SMX versus co-amoxiclav versus no treatment Montini et al. (2008)
None
0.26–1.24
>0.05 HR: 0.57 338 (98 vs 113 vs 127)
[47]
TMP–SMX versus placebo PRIVENT trial
Double-blinded
0.40–0.93
0.02 HR: 0.61 576 (288 vs 288)
[110]
0.0002 Not reported Febrile UTI occurred in 14/66 versus 10/69 versus 25/68 Endoscopic treatment versus antibiotic prophylaxis versus surveillance Swedish reflux trial in children
None
203 (66 vs 69 vs 68)
[21]
0.002 0.34–0.74 HR: 0.50 TMP–SMX versus placebo RIVUR trial
Double-blinded
607 (302 vs 305)
p-value 95% CI Outcome measure Sample size Blinding Treatment groups Study (year)
Table 3. Randomized trials evaluating the efficacy of antimicrobial prophylaxis for preventing recurrent urinary tract infections in children†.
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such definitive evidence, it would be unreasonable to conclude that antibiotic prophylaxis in susceptible children is harmful in the long run. Despite the completion of several randomized controlled trials, there is still some debate over the routine use of antimicrobial prophylaxis in all children with VUR and/or recurrent UTI [118]. The choice of antimicrobial agents for prophylaxis and adequate duration of such therapy also remain unsettled, although in most clinical trials, nitrofurantoin (1 mg/kg/day) or TMP–SMX (2 mg/kg/day of trimethoprim) has been used for chemoprophylaxis [21,47,110]. With the currently available literature, the decision to prescribe antimicrobial prophylaxis remains at the discretion of the treating pediatrician and should be considered on a case-bycase basis [16]. Watchful waiting with prompt recognition and treatment of UTI may be appropriate for children with low-grade VUR and/or at low risk of recurrent UTI [17]. On the other hand, surgery or endoscopic treatment may be considered for children with worsening renal function despite antimicrobial prophylaxis [18,20]. Endoscopic & surgical management of VUR
Surgical management for VUR has been in practice ever since the association between VUR and pyelonephritis was recognized. As discussed previously (see section ‘Introduction’), the ureterovesical junction is not guarded by an anatomic sphincter; the oblique insertion of ureter into the trigone of bladder acts as a functional sphincter during micturition. Consequently, surgical and endoscopic treatment of VUR aims to reinforce this functional sphincter by various means in the hope of curing VUR [119]. Such interventions were routinely used for children found to have high-grade VUR on VCUG in the traditional ‘bottom-up’ approach [61]. With advances in our knowledge and the recognition that VUR may improve with age, surgical management has been relegated to a last resort of treatment for children with VUR and recurrent UTI [18]. Guidelines formulated by both the AUA and EAU recommend that surgical management should be reserved for children in high-risk groups (BOX 4) [18,20]. Infants and young (
Review
Evaluation and management of recurrent urinary tract infections in children: state of the art Expert Rev. Anti Infect. Ther. 13(2), 209–231 (2015)
Muhammad Awais*1, Abdul Rehman2, Noor Ul-Ain Baloch2, Farid Khan3 and Naseer Khan4 1 Department of Radiology, Aga Khan University Hospital, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 2 Department of Biological and Biomedical Sciences, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 3 Department of Surgery, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan 4 Department of Pediatrics, Aga Khan University, P.O. box 3500, Stadium Road, Karachi 74800, Sindh, Pakistan *Author for correspondence: Tel.: +92 300 903 4827 [email protected]
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Urinary tract infections (UTIs) represent an important cause of febrile illness in young children and can lead to renal scarring and kidney failure. However, diagnosis and treatment of recurrent UTI in children is an area of some controversy. Guidelines from the American Academy of Pediatrics, National Institute for Health and Clinical Excellence and European Society of Paediatric Radiology differ from each other in terms of the diagnostic algorithm to be followed. Treatment of vesicoureteral reflux and antibiotic prophylaxis for prevention of recurrent UTI are also areas of considerable debate. In this review, we collate and appraise recently published literature in order to formulate evidence-based guidance for the diagnosis and treatment of recurrent UTI in children. KEYWORDS: antibiotic prophylaxis . cystitis . pyelonephritis . urinary tract anomalies . urinary tract infection .
vesicoureteral reflux
Urinary tract infection (UTI) is an important cause of febrile illness among young children throughout the world. It has been estimated that by the age of 6 years, 2% of boys and 7% of girls would have experienced at least one symptomatic UTI [1]. A meta-analysis of 14 prevalence studies, published in 2008, observed that the prevalence of UTI among febrile children was highest in uncircumcised boys under the age of 3 months (pooled prevalence of 20.1%) and girls aged 6–12 months (pooled prevalence of 8.3%) [2]. Even among older children (5 years) may report specific urinary complaints, such as frequency, burning micturition and offensive urine. UTI may also present in toilet-trained children as new-onset urinary incontinence or bed-wetting. However, several studies published in the past few decades have also recognized UTI as an important cause of febrile illness in children [24]. This finding underscores the importance of considering UTI in the differential diagnosis of any child presenting with fever. Laboratory testing of urine specimens is both useful and essential for making a diagnosis of UTI. Three different types of tests are commonly performed on urine specimens – urine dipstick, microscopy and culture. Urine dipstick, which is often performed at the patient’s bedside, can indicate the presence of leukocyte esterase and nitrite. Sensitivity and specificity of leukocyte esterase alone have been reported to be approximately 79 and 87%, respectively, while these values for nitrite alone are around 49 and 98%, respectively [25]. When the two tests are used together, sensitivity increases to 87%, while specificity goes down to 79% [25–27]. Urine microscopy allows direct visualization of leukocytes and bacteria in the urine. In most laboratories, urine dipstick and microscopy are performed and reported together (‘urinalysis’). This urinalysis confers a higher sensitivity of 99.8% with a specificity of 70% [19,25]. Urine culture not only detects the presence of bacteria in the urine but also provides information about the sensitivity patterns. However, a prerequisite for urine culture and sensitivity is an uncontaminated sample of urine. While a clean-catch, midstream sample of urine can be obtained satisfactorily in older children, this is not possible in infants and younger children. For such children, catheterization can provide an uncontaminated sample of urine for culture. However, in certain cases (labial adhesions, phimosis), even catheterization may not be possible; suprapubic aspiration of bladder can provide a clean sample of urine for culture in such patients. High-quality evidence has shown that culture of urine obtained by catheterization has a sensitivity and specificity of 95 and 99%, respectively, which are comparable to those obtained by suprapubic aspiration [28,29]. For a diagnosis of UTI, quantification of bacterial growth on urine culture is important. This is because voided urine specimens can be contaminated by distal urethral and perineal flora. For clean-catch, midstream urine samples, growth of ‡100,000 CFU/ml of a known uropathogen suggests UTI or asymptomatic bacteriuria. When a urine specimen has been obtained by catheterization, growth of ‡10,000 CFU/ml of a pathogenic bacterium is also considered significant. In samples obtained by suprapubic aspiration, even growth of a single organism is considered abnormal [1,23,30]. informahealthcare.com
Review
4514 articles identified by initial search
756 duplicate entries
1673 deemed irrelevant
2085 abstracts reviewed
820 focused on adults
126 focused on first UTI
1139 full-text retrieved 23 additional articles identified through reference lists 57 focused on irrelevant aspects
1105 articles included
SR/MA Clinical trials Observational studies Secondary literature
22 33 408 642
Figure 1. A flow chart depicting the inclusion and exclusion of articles for the purpose of this review. MA: Meta-analyses; SR: Systematic reviews; UTI: Urinary tract infection.
In clinical practice, urinalysis and urine culture are used together in conjunction with the patient’s clinical features to make a diagnosis of UTI. Urinalysis is warranted in all children who present with clinical features suggestive of a UTI [22]. Evidence supports routinely obtaining urinalysis in febrile children with no apparent source of infection [31]. In febrile children for whom empiric antibiotic therapy has to be instituted, urinalysis along with urine culture and sensitivity should be obtained prior to the start of antimicrobial therapy. Urine culture should also be obtained in children with a positive urinalysis before starting antimicrobial treatment [16,19]. While examination of urine specimens can provide evidence of a UTI, such investigations cannot differentiate between infections of the lower (cystitis) and upper (pyelonephritis) urinary tract. Studies have shown that the presence of high-grade fever or severe illness is highly predictive of pyelonephritis. Furthermore, pyelonephritis is also suggested by the presence of flank pain or tenderness [16,32]. Definitive diagnosis of 211
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Awais, Rehman, Baloch, Khan & Khan
pyelonephritis can be made with the help of radionuclide imaging of the kidneys [33]. However, differentiation between upper and lower UTI often does not alter the immediate management of a patient. Therefore, routine use of diagnostic imaging for localization of UTI is not justified [34].
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Etiology of UTI
While adenovirus and Candida spp. can cause UTI in children, the vast majority of UTI in children are due to bacterial pathogens [23]. The most common bacterial pathogens isolated are gram-negative rods (E. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas spp.) and gram-positive cocci (Streptococcus agalactiae, Enterococcus spp.) [35]. Some studies have demonstrated sex- and age-specific trends. E. coli more commonly infects neonatal boys than girls [36]. Likewise, uncircumcised boys are more prone to develop UTI due to Proteus spp., while Staphylococcus spp. frequently infect adolescent girls [37,38]. The role of certain host (uropathogenic colonic flora, perimeatal colonization in uncircumcised boys, short urethra in girls, LUTD, VUR) and bacterial (lipopolysaccharide, K capsular antigen, hemolysin, aerobactin, p-fimbriae) virulence factors in the pathogenesis of UTI is well established [10,39]. Recent research has shown that innate immunity and urinary tract responses also play a crucial role in the development of UTI [9]. Genetic polymorphisms in the genes for HSPA1B, TLR4, CXCR1, CXCR2, IL-8 and IL-10 have been shown to predispose patients to the development of UTI [40–42]. New virulence characteristics, such as the formation of biofilms and intracellular bacterial communities, have been identified that allow the persistence of uropathogenic bacteria and recurrence of UTI [43,44]. Resistance of uropathogenic organisms to traditional antibiotics is increasing over time and this poses a major public health concern for both developed and developing countries [45]. A meta-analysis of antimicrobial resistance among neonatal pathogens in developing countries reported that resistance of E. coli to ampicillin and trimethoprim–sulfamethoxazole (TMP–SMX) was 72 and 78%, respectively. Similarly, resistance of Klebsiella spp. to gentamicin and third-generation cephalosporins was 60 and 66%, respectively [46]. Routine antibiotic prophylaxis with TMP-SMX may also increase the prevalence of TMP-SMX-resistant organisms [21,47,48]. In vitro studies have shown that in children prescribed TMP–SMX for longterm prophylaxis, E. coli strains tend to rapidly acquire antibiotic resistance genes [49]. Treatment of active UTI
Prompt recognition and treatment of UTI is essential and evidence has shown that delaying treatment in young children with UTI while awaiting results of laboratory investigations is harmful [30]. Children who have clinical features highly suggestive of UTI and positive urine dipstick and/or microscopy should be started on empiric antibiotic therapy. Furthermore, in children with high-grade fever or signs of severe illness, empiric antibiotic treatment should be started after sending urine for urinalysis and culture [16,19,24]. 212
Choice of antibiotics for empiric treatment of patients with suspected UTI should be based on local data of antibiotic susceptibility. Empiric antimicrobial agents should have appropriate activity against gram-negative rods and gram-positive cocci [35]. The empiric agent should be switched to an appropriate antimicrobial agent depending on the results of urine culture and sensitivity. In the past, amoxicillin and TMP–SMX were used as empiric antibiotics. However, due to increasing resistance to these drugs, many pediatricians now prefer to use cephalosporins (cephalexin, cefpodoxime and cefixime) or amoxicillin–clavulanate as empiric agents [45,46]. Dosage of common antimicrobial agents is summarized in TABLE 1. Traditionally, children diagnosed to have cystitis were treated orally, while those with acute pyelonephritis were started on intravenous antibiotics. However, several studies have shown that treatment of UTI (both cystitis and acute pyelonephritis) with oral antibiotics is as safe and effective as parenteral therapy [50–53]. In a clinical trial by Bocquet et al., there was no difference in resolution of fever or presence of renal scar at 6 months among those treated with intravenous ceftriaxone plus oral cefixime versus those treated with oral cefixime alone [54]. In another multicenter randomized clinical trial, Hoberman et al. found no significant difference in the incidence of recurrent UTI among children treated with oral antibiotics alone versus those treated initially with intravenous antibiotics [55]. Parenteral antimicrobial therapy may be appropriate for children who are unable to tolerate orally or appear systemically unwell. Third-generation cephalosporins or a combination of ampicillin and gentamicin are the commonly used intravenous antibiotics [16,19]. Duration of therapy for UTI has also been validated by some studies. Some evidence suggests that single-day antibiotic regimens are harmful in children with UTI [56]. Three-day regimens of TMP–SMX or nitrofurantoin are acceptable for older (>3 years) children with typical features of uncomplicated cystitis [57]. Many studies have also shown that outcome of children with pyelonephritis treated with a short (3–4 days) course of antibiotics versus those treated with a longer (7–10 days) course of antibiotics is similar [51,52,58,59]. Recommendations of treating younger (3 years) children with complicated UTI or pyelonephritis with a 10-day course of antibiotics are based on expert advice [16,19]. It has also been suggested that antimicrobials which achieve therapeutic concentrations only in the urine, such as nitrofurantoin, should not be used to treat pyelonephritis [19]. This is based on the presumption that serum antimicrobial concentrations are not sufficient to prevent the development of urosepsis and septic shock. Diagnostic imaging modalities
Diagnostic imaging for children with recurrent UTI is a constantly evolving field and no single diagnostic algorithm is agreed upon by all. Different approaches have been proposed for imaging young children with recurrent UTI. However, certain key principles are common to all these approaches, as explained below. Expert Rev. Anti Infect. Ther. 13(2), (2015)
Evaluation & management of recurrent UTIs in children
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Table 1. Common antibiotics used for the treatment of urinary tract infections. Antibiotic
Class of agent
Route
Dosage
Adverse effects
Amoxicillin
Penicillin
Oral
40 mg/kg/day in three divided doses
Ampicillin
Parenteral
100 mg/kg/day in four divided doses
Allergy, rash, GI disturbance, pseudomembranous colitis
Amoxicillin–clavulanate
Oral, parenteral
40 mg/kg/day of amoxicillin in three divided doses
Piperacillin
Parenteral
200–300 mg/kg/day in four divided doses
Oral
50 mg/kg/day in three to four divided doses
Cefixime
Oral
8 mg/kg/day in one to two divided doses
Cefotaxime
Parenteral
100–200 mg/kg/day in three to four divided doses
Ceftazidime
Parenteral
100–150 mg/kg/day in three divided doses
Ceftriaxone
Parenteral
50–75 mg/kg/day
Cefpodoxime
Oral
10 mg/kg/day in two divided doses
Parenteral
7.5 mg/kg/day in three divided doses
Parenteral
15 mg/kg/day in one to three divided doses
Oral
6–12 mg/kg/day of trimethoprim in two divided doses
Cephalexin
Gentamicin
Cephalosporin
Aminoglycoside
Amikacin Trimethoprim– sulfamethoxazole
Sulfonamide
Allergy, rash, GI distress, pseudomembranous colitis, cholestasis†
Nephrotoxicity, ototoxicity
Steven–Johnson syndrome, myelosuppression, hepatotoxicity
† Cholestasis frequently occurs in neonates treated with ceftriaxone. GI: Gastrointestinal.
The ‘bottom-up’ approach was conventionally used in the past for evaluation of children with UTI. This approach was based on the proposition that children with VUR are more prone to develop pyelonephritis, and therefore, children presenting with a UTI must be evaluated for the presence of VUR [60]. Voiding cystourethrography (VCUG) was routinely performed in children who had experienced a febrile UTI [61]. This contrast-enhanced fluoroscopic study was not only invasive but also exposed young children to a significant radiation dose [62]. Identification of VUR in children would prompt imaging of the kidneys to detect the presence of renal scarring and institution of antibiotic prophylaxis or surgery to treat VUR. In this approach, emphasis was on the detection of VUR that would provide the opportunity to prevent further renal damage. The ‘bottom-up’ approach was not supported by evidence accumulated over the past several decades. Studies showed that many children developed pyelonephritis and renal scars, even in the absence of VUR [63,64]. Furthermore, many studies suggested that prompt recognition and treatment of children with pyelonephritis was better than subjecting all children with VUR to antibiotic prophylaxis and/or surgery [65–68]. It was also observed that many children with VUR improved over
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time and did not develop pyelonephritis [69,70]. While VCUG was sufficiently accurate in the detection of VUR, yield of VCUG in the ‘bottom-up’ approach was quite low (~1%) and this entailed unnecessary radiation exposure and discomfort for a significant proportion of children [19,71]. Consequently, in the light of new evidence, a ‘top-down’ approach to diagnostic imaging was adopted. The ‘top-down’ approach for diagnostic imaging shifted the focus from identification of children with VUR to identification of children at risk of developing renal scars (FIGURE 2). Studies reported from the USA demonstrated that third-trimester antenatal ultrasonography was effective in detecting most clinically significant urinary tract anomalies [72,73]. Therefore, in children with documented normal antenatal imaging, clinically significant urinary tract abnormalities are unlikely, even in the presence of UTI [74,75]. However, fetuses identified to have antenatal hydronephrosis require ultrasonography after birth along with radionuclide renal scanning and/or VCUG [17]. As for children who develop UTI, guidelines differ in the indications for various imaging modalities and the exact protocol to be followed (BOX 2). Guidelines developed by the American Academy of Pediatrics, National Institute for Health and Clinical Excellence and
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Awais, Rehman, Baloch, Khan & Khan
Febrile UTI
Bottom-up approach
Continue follow-up
DMSA scan
Renal scars noted
Normal
Renal scarring
Normal
Consider antibiotic prophylaxis
Consider antibiotic prophylaxis VCUG
Top-down approach
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Normal
Abnormal
Consider surgical or endoscopic intervention
DMSA scan
U/S
VUR < grade IV
VUR present Febrile UTI
VCUG
VUR absent
Continue follow-up
VUR grade IV–V Consider surgical or endoscopic intervention
Figure 2. A comparison of the ‘bottom-up’ and ‘top-down’ approaches of diagnostic imaging. DMSA: Dimercaptosuccinic acid; U/S: Ultrasonography; UTI: Urinary tract infection; VCUG: Voiding cystourethrography; VUR: Vesicoureteral reflux.
European Society of Paediatric Radiology are based on some common considerations about various diagnostic imaging modalities. Imaging of the kidneys by ultrasonography and/or renal scintigraphy can be performed either during the febrile illness (to diagnose pyelonephritis) or several months later (to detect renal scars). Ultrasonography is known to have a low accuracy for predicting VUR or even pyelonephritis [76,77]. However, in children with normal antenatal imaging, performing an ultrasound will help to identify only those children who have clinically significant hydronephrosis or scarring. Children with mild and clinically insignificant VUR may be missed in such an approach; however, VUR in such children is usually inconsequential and, in most cases, will resolve with age [78]. Dimercaptosuccinic acid (DMSA) renal scintigraphy has been shown to be the most accurate imaging modality for detecting pyelonephritis and renal scarring [79]. DMSA, during acute illness, is generally reserved for children with an abnormal ultrasound, or those with a normal ultrasound and a high clinical suspicion of pyelonephritis [16,17]. On the other hand, DMSA is routinely used in young children with recurrent UTI to assess renal function and quantify renal scarring [80]. Although DMSA entails exposure to radiation, the dose is much lower compared to VCUG [81]. In the ‘top-down’ approach, VCUG is reserved only for patients who have abnormal ultrasonography and evidence of renal damage on DMSA scans. This approach confers excellent accuracy for detecting high-grade VUR (TABLE 2) [33,82–88]. Moreover, it obviates the need of VCUG in almost 50% of children, who
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would otherwise be subjected to VCUG in a ‘bottom-up’ approach. Newer imaging modalities are currently being investigated in order to develop a modality that would non-invasively diagnose VUR. Contrast-enhanced voiding urosonography has shown some promise for the detection of VUR in young girls [89]. However, this technique is time consuming, operator dependent and not widely available [90]. Radionuclide cystography has been proposed as an alternative to VCUG for the detection of VUR with an acceptable accuracy and radiation dose [91]. More recently, magnetic resonance urography has been employed for the detection of renal scarring in children with recurrent UTI [92]. MR–VCUG may be equivalent to conventional VCUG in detecting VUR without the associated radiation hazard [93]. More evidence is needed before these newer imaging modalities can be recommended for routine use in clinical practice. Another area that merits attention is screening of siblings of children diagnosed to have VUR. Studies have shown that VUR tends to run in families and screening of siblings can allow detection of asymptomatic VUR at earlier grades [94,95]. Furthermore, VUR detected in siblings after a UTI is often high grade and associated with renal scarring [96]. Some studies have also reported the presence of high-grade VUR and renal scarring in asymptomatic siblings [97]. While these studies suggest that screening of siblings should be performed, there is insufficient evidence to support a single diagnostic algorithm [98]. Expert advice is to obtain renal ultrasonography
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Box 2. Diagnostic imaging algorithms recommended by the National Institute of Health and Clinical Excellence, the European Society of Paediatric Radiology and the American Academy of Pediatrics. NICE . .
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.
. .
Routine imaging for children with a first UTI is not recommended Ultrasound during the acute phase should only be performed in cases of an ‘atypical UTI’ (septicemia, raised serum creatinine, abdominal mass, failure to respond to treatment within 48 h, infection with an organism other than Escherichia coli, poor urine flow or seriously ill child) Ultrasound after 6 weeks may be performed for children with recurrent UTI (defined as ‡2 episodes of pyelonephritis, or ‡3 episodes of cystitis, or 1 episode of pyelonephritis along with ‡1 episode of cystitis) or for those with a first UTI below the age of 3 months DMSA scan should be performed in children with atypical or recurrent UTI 4–6 months after the acute infection VCUG is to be performed only in those children who are under the age of 3 months and have experienced atypical or recurrent UTI
AAP . . . .
Children of age 2–24 months should routinely undergo renal and bladder ultrasonography during a febrile UTI If ultrasonography reveals hydronephrosis, scarring or any other signs of obstructive uropathy, VCUG should be performed VCUG should also be performed in other atypical or complex clinical situations Children who experience recurrence of a febrile UTI should be evaluated further
ESPR .
.
. .
.
. .
Routine imaging is not recommended for children with a UTI who have documented, normal, antenatal (third-trimester) ultrasonography and not have atypical clinical features Ultrasound with amplitude-coded color Doppler should be performed during the acute phase for children less than 1 year of age or those older than 1 year of age with serious illness Children with a normal ultrasound do not need further follow-up In cases where ultrasound is equivocal and clinical suspicion of pyelonephritis is high, acute-phase DMSA scan should be performed Children with evidence of pyelonephritis on DMSA scan or ultrasonography require: follow-up ultrasound after resolution of UTI; DMSA scan after 6–12 months; and evaluation for VUR if less than 1 year of age, or 1–5 years of age with abnormal follow-up ultrasonography, or greater than 5 years of age with recurrent UTI Evaluation of VUR should be performed by VCUG in boys and ce-VUS in girls (if available) Follow-up of VUR should be performed by RNC or ce-VUS
AAP: American Academy of Pediatrics; ce-VUS: Contrast-enhanced voiding urosonography; DMSA: Dimercaptosuccinic acid; ESPR: European Society of Paediatric Radiology; NICE: National Institute of Health and Clinical Excellence; RNC: Radionuclide cystography; UTI: Urinary tract infection; VCUG: Voiding cystourethrography; VUR: Vesicoureteral reflux.
along with DMSA scintigraphy to detect renal injury or scarring [99]. Routine VCUG for screening siblings is not recommended; VCUG should only be performed in siblings found to have significant renal scarring and/or compromised renal functions on DMSA scintigraphy [18,20]. European Society of Paediatric Radiology has also included contrast-enhanced voiding urosonography as a non-invasive screening modality for siblings of children diagnosed with VUR [17]. Antimicrobial prophylaxis
One of the rather controversial areas in the management of recurrent UTI is antimicrobial prophylaxis. Initially, when the association between pyelonephritis and VUR was recognized, treatment for VUR was thought to prevent renal scarring and its associated long-term complications [100]. Antimicrobial prophylaxis was proposed as a method to prevent recurrent UTI and subsequent renal damage. Surgery was performed for patients who had persistent VUR or developed UTI despite
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antimicrobial prophylaxis. This strategy was thought to prevent the development of renal scars, thereby reducing the incidence of hypertension, pre-eclampsia and end-stage renal disease [101]. Several studies published over the last two decades have challenged this notion [65,102]. Many studies have demonstrated that pyelonephritis can develop even in the absence of VUR [63,64]. Earlier studies, which reported a high prevalence of renal scars among children with recurrent UTI, were performed at a time when antenatal imaging was not widely available [103]. With the implementation of routine third-trimester ultrasonography, most congenital renal abnormalities (including antenatal hydronephrosis) began to be detected before the development of a UTI [72–75]. Prospective studies performed in children without any urinary tract malformations (other than VUR) failed to reveal any association between the development of pyelonephritis and subsequent renal dysfunction [104,105]. These studies suggested that pyelonephritis often resulted in the formation of small cortical scars, which were inconsequential in the long 215
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Table 2. Accuracy of ultrasonography vis-a`-vis dimercaptosuccinic acid scan for predicting high-grade (III–V) vesicoureteral reflux on voiding cystourethrography. Study (year)
Diagnostic modality
Sensitivity (%)
Specificity (%)
Awais et al. (2014)
Ultrasonography
100
18
DMSA scan
95.45
35.71
Both modalities abnormal
95.45
60.71
Either modality abnormal
100
17.86
Ultrasonography
83.33
61.18
DMSA scan
83.33
68.64
Both modalities abnormal
72.92
81.49
Either modality abnormal
93.75
48.33
Mantadakis et al. (2011)
DMSA scan
71
67
[33]
Fouzas et al. (2010)
DMSA scan
76
63.5
[84]
Lee et al. (2009)
Ultrasonography
67.2
46.2
[85]
DMSA scan
65.5
63.8
Either modality abnormal
83.2
38.6
Preda et al. (2007)
DMSA scan
96
57.6
[86]
Tseng et al. (2007)
DMSA scan
100
34
[87]
Hansson et al. (2004)
DMSA scan
80.55
80.9
[88]
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Quirino et al. (2011)
Ref. [82]
[83]
DMSA: Dimercaptosuccinic acid.
run [9]. Studies performed in adolescents with chronic renal failure also observed that recurrent pyelonephritis was not a leading cause of end-stage renal disease [106]. In the light of these studies, the actual benefit of antimicrobial prophylaxis for children with VUR became questionable. Several randomized controlled trials were completed between the years 2006 and 2014. Results of four randomized controlled trials failed to show any benefit of antimicrobial prophylaxis [107–109]. On the other hand, three randomized controlled trials were able to demonstrate statistically significant, but clinically modest, benefit from TMP–SMX prophylaxis (TABLE 3) [21,47,110]. Three different meta-analyses and/ or systematic reviews were published during the same period and gave conflicting conclusions (TABLE 4) [111–114]. The most recent systematic review by Williams and Craig reported that antimicrobial prophylaxis likely provided a modest reduction in the frequency of recurrent UTI [111]. However, this conclusion was based on the results of only two randomized controlled trials, of which one did not report any statistically significant benefit of antimicrobial prophylaxis [47,107]. Williams and Craig argued that pooled results inclusive of other randomized trials provided imprecise point estimates with marked heterogeneity [111]. Consistent with their observation, the largest (and also the most recent) randomized study, the RIVUR trial, showed a modest reduction in recurrence of UTI in children administered TMP–SMX prophylaxis (BOX 3) [21]. (It is noteworthy that this study had not been completed when the systematic review
216
by Williams and Craig was published in 2011.) A meta-analysis of all seven trials shows a definitive benefit of prophylactic antibiotics (FIGURE 3). However, even the RIVUR study failed to show a significant difference in the incidence of renal scars among children who received placebo versus those who received TMP–SMX. While some reduction in the frequency of recurrent UTI may be achieved with TMP–SMX prophylaxis, this benefit has to be weighed against the potential harms associated with antimicrobial prophylaxis. There were fewer side effects associated with TMP–SMX prophylaxis in most randomized trials [21,47,107]. However, this risk of adverse effects should be considered in conjunction with the need to administer 16 patientyears of TMP–SMX to prevent a single UTI (as inferred from the RIVUR study) [21]. Another concern is the increase in antibiotic-resistant virulent organisms, which may potentially lead to serious infections [115]. In most randomized trials, children receiving antibiotic prophylaxis were more prone to develop infections due to resistant organisms [21,47,107]. Some studies suggest that oral administration of prophylactic antibiotics can change the pattern of enteric flora favoring a preponderance of antibiotic-resistant bacteria [116]. Such organisms may potentially cause serious infections in close family members of the patient. While these concerns do seem valid, large-scale studies of children followed for several (15–20) years would be needed to quantify the harm resulting from antimicrobial prophylaxis vis-a`-vis the benefit obtained [117]. In the absence of
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[214]
0.68–2.11
>0.05 RR: 1.233 100 (50 vs 50) None TMP–SMX versus no treatment
Studies published before the year 2005 are not tabulated here. HR: Hazard ratio; PRIVENT: Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteral Reflux and Normal Renal Tracts; RIVUR: Randomized Intervention for Children with Vesicoureteral Reflux; RR: Relative risk; TMP–SMX: Trimethoprim–sulfamethoxazole; UTI: Urinary tract infection; VUR: Vesicoureteral reflux.
Pennesi et al. (2006)
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†
[109]
0.9 and 0.06 for the two groups Rate of UTI in children with VUR: 22.4 versus 23.3%; rate of UTI in children without VUR: 8.8 versus 23.6% VUR (treatment vs none) and no VUR (treatment vs none) Garin et al. (2006)
None
218 (55 vs 58 and 45 vs 60)
[108]
>0.05 TMP–SMX versus no treatment Roussey-Kesler et al. (2008)
None
Not reported UTI occurred in 18/ 103 versus 32/122 225 (103 vs 122)
[107]
TMP–SMX versus co-amoxiclav versus no treatment Montini et al. (2008)
None
0.26–1.24
>0.05 HR: 0.57 338 (98 vs 113 vs 127)
[47]
TMP–SMX versus placebo PRIVENT trial
Double-blinded
0.40–0.93
0.02 HR: 0.61 576 (288 vs 288)
[110]
0.0002 Not reported Febrile UTI occurred in 14/66 versus 10/69 versus 25/68 Endoscopic treatment versus antibiotic prophylaxis versus surveillance Swedish reflux trial in children
None
203 (66 vs 69 vs 68)
[21]
0.002 0.34–0.74 HR: 0.50 TMP–SMX versus placebo RIVUR trial
Double-blinded
607 (302 vs 305)
p-value 95% CI Outcome measure Sample size Blinding Treatment groups Study (year)
Table 3. Randomized trials evaluating the efficacy of antimicrobial prophylaxis for preventing recurrent urinary tract infections in children†.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/17/15 For personal use only.
Ref.
Evaluation & management of recurrent UTIs in children
Review
such definitive evidence, it would be unreasonable to conclude that antibiotic prophylaxis in susceptible children is harmful in the long run. Despite the completion of several randomized controlled trials, there is still some debate over the routine use of antimicrobial prophylaxis in all children with VUR and/or recurrent UTI [118]. The choice of antimicrobial agents for prophylaxis and adequate duration of such therapy also remain unsettled, although in most clinical trials, nitrofurantoin (1 mg/kg/day) or TMP–SMX (2 mg/kg/day of trimethoprim) has been used for chemoprophylaxis [21,47,110]. With the currently available literature, the decision to prescribe antimicrobial prophylaxis remains at the discretion of the treating pediatrician and should be considered on a case-bycase basis [16]. Watchful waiting with prompt recognition and treatment of UTI may be appropriate for children with low-grade VUR and/or at low risk of recurrent UTI [17]. On the other hand, surgery or endoscopic treatment may be considered for children with worsening renal function despite antimicrobial prophylaxis [18,20]. Endoscopic & surgical management of VUR
Surgical management for VUR has been in practice ever since the association between VUR and pyelonephritis was recognized. As discussed previously (see section ‘Introduction’), the ureterovesical junction is not guarded by an anatomic sphincter; the oblique insertion of ureter into the trigone of bladder acts as a functional sphincter during micturition. Consequently, surgical and endoscopic treatment of VUR aims to reinforce this functional sphincter by various means in the hope of curing VUR [119]. Such interventions were routinely used for children found to have high-grade VUR on VCUG in the traditional ‘bottom-up’ approach [61]. With advances in our knowledge and the recognition that VUR may improve with age, surgical management has been relegated to a last resort of treatment for children with VUR and recurrent UTI [18]. Guidelines formulated by both the AUA and EAU recommend that surgical management should be reserved for children in high-risk groups (BOX 4) [18,20]. Infants and young (
