Urinary Tract Infection: Clinical Guidelines

List of Abbreviations

ABT – antibiotic therapy

ESBL – extended-spectrum beta-lactamases

UTI – urinary tract infection

IL – interleukin

CFU — colony-forming unit

Med – medication

UT – urinary tract

INN – International Nonproprietary Name

MRI – magnetic resonance imaging

PCT – procalcitonin

SYS – systemic antimicrobial drugs

VUR – vesicoureteral reflux

CRP – C-reactive protein

US – ultrasound examination

Pelvicalyceal system – pelvicalyceal system

E. coli – Escherichia coli

EANM – The European Association of Nuclear Medicine,

E.faecalis – Enterococcus faecalis

K. pneumoniae – Klebsiella pneumoniae

MRSE – methicillin-resistant Staphylococcus epidermidis

MRSA – methicillin-resistant Staphylococcus aureus

P. aeruginosa – Pseudomonas aeruginosa

S. saprophyticus – Staphylococcus saprophyticus

S. aureus – Staphylococcus aureus

SNMMI – The Society of Nuclear Medicine and Molecular Imaging

** – a medicinal product included in the Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on June 9, 2023) <On approval of the list of vital and essential drugs, as well as lists of medicinal products for medical use and the minimum assortment of medicinal products required for the provision of medical care>.

# – The use of a medicinal product in accordance with indicators (characteristics) not specified in its instructions for use (off-label) is carried out by the decision of the medical commission, subject to a signed informed voluntary consent (pursuant to Federal Law No. 323-FZ of November 21, 2011, as amended).

Terms and Definitions

New and narrowly focused professional terms are not used in these clinical guidelines.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Urinary tract infection (UTI) – an inflammatory process of the urothelium in various sections of the urinary tract, arising in response to the appearance of pathogenic microorganisms in the urinary tract.

Bacteriuria – the presence of bacteria in urine isolated from the bladder.

Asymptomatic bacteriuria – the presence of one or more species of bacteria growing in urine in an amount of more than 10⁵ CFU/mL, regardless of the presence of pyuria, in the absence of any complaints and clinical symptoms of the urinary system disease. It can be detected during routine or targeted examination of a child.

Acute pyelonephritis – an inflammatory disease of the renal parenchyma and pelvis resulting from a bacterial infection.

Acute cystitis – an inflammatory disease of the bladder of bacterial origin.

Chronic pyelonephritis – renal damage manifested by fibrosis and deformation of the pelvicalyceal system as a result of recurrent UTI attacks. As a rule, it occurs against the background of anatomical anomalies of the urinary tract or obstruction.

Vesicoureteral reflux (VUR) – retrograde flow of urine from the bladder into the ureter.

Reflux nephropathy – focal or diffuse sclerosis of the renal parenchyma, the primary cause of which is vesicoureteral reflux leading to intrarenal reflux, recurrent attacks of pyelonephritis, and sclerosis of the renal tissue.

Urosepsis – a life-threatening generalized pathological process accompanied by organ/multiple organ dysfunction, in which the clinical manifestations of UTI are complicated by the body's reaction to the infection, damaging its own tissues and organs.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Among the causative agents of UTIs in children, gram-negative flora predominates, while community-acquired infection variants are significantly dominated by members of the order Enterobacterales and, in particular, E. coli (70-90% of cases). Gram-positive microorganisms are rarely found as an etiological factor and are represented mainly by enterococci and staphylococci (5-7% of all UTI cases). In addition, hospital-acquired (nosocomial) infections are distinguished, among the causative agents of which gram-negative microorganisms of the order Enterobacterales ssp. also predominate, but non-fermenting gram-negative pathogens (Pseudomonas spp., Acinetobacter spp.) may also be isolated. In newborns, group A and B streptococci are relatively frequent causes of UTIs. Recently, an increase in the detection of S. saprophyticus has been noted, although its role remains controversial.

According to the large multicenter study "DARMIS-2018" conducted in 2017-2018, the similarity of the etiological structure of community-acquired UTIs in various subpopulations of patients with acute and exacerbations of chronic UTIs (children, adults, pregnant women) was demonstrated, which generally corresponds to the results obtained earlier [1]. The total share of members of the order Enterobacterales in children with community-acquired UTIs in HA was 93.8%, the isolation rate of E. coli was about 80%, and that of the second most frequent uropathogen K. pneumoniae was 8%.

Data on the resistance of the main uropathogen E. coli in community-acquired UTIs in children in the Russian Federation were analyzed within the framework of the "DARMIS-2023" project.

More than 60% of E. coli isolates from UTIs in children in the Russian Federation are resistant to ampicillin** (63.4%). Regarding susceptibility to Amoxicillin+[Clavulanic acid]**, it is necessary to dwell on the differences in data interpretation (EUCAST v13.0 (2023)) for oral dosage forms of Amoxicillin+[Clavulanic acid]** in uncomplicated UTIs and parenteral forms of the drug. For oral forms (used in uncomplicated UTIs), the proportion of susceptible strains with MIC ≤32 mg/L is 87%; for parenteral forms of Amoxicillin+[Clavulanic acid]**, the proportion of susceptible strains with MIC ≤8 mg/L is 63.6%. It is precisely because of these features that the place of Amoxicillin+[Clavulanic acid]** in the recommendations for drug selection for outpatient prescription and in the hospital will differ. For other ABPs, the situation is as follows: 76.6% of isolated E. coli strains are susceptible to the drug Co-trimoxazole [Sulfamethoxazole+Trimethoprim]**; susceptibility to third- and fourth-generation cephalosporins ranges from 82% to 87%.

The highest susceptibility rates of E. coli to oral ABPs were demonstrated for fosfomycin** (98.7%) and nitrofurantoin (97.4%). Among parenteral ABPs, 100% activity is noted for carbapenems (Imipenem+[Cilastatin]** and Meropenem**) and 98.7% for ertapenem**; high susceptibility is maintained to amikacin** (98.7%), gentamicin** (94.8%), fosfomycin** (98.7%), and piperacillin+[tazobactam] (98.1%).

Among the numerous factors contributing to the development of UTIs, anomalies of UTI development and urodynamic disorders (VUR, obstructive uropathy, neurogenic bladder dysfunction) are of priority importance, as well as the biological properties of microorganisms colonizing the renal tissue (e.g., the presence of fimbriae in E. coli, which promotes not only attachment to the urothelium and penetration through it, but also the formation of bacterial conglomerates and biofilms).

The ascending pathway is considered the most frequent route of infection spread. The reservoir of uropathogenic bacteria is the rectum, perineum, and lower urinary tract.

Anatomical features of the female urinary tract (short wide urethra, proximity of the anorectal area) determine the high incidence and recurrence rate of UTIs in girls and young women.

In the ascending pathway of UTI spread, after bacteria overcome the vesicourethral barrier, their rapid reproduction occurs with the release of endotoxins. In response, the local immunity of the host organism is activated: activation of macrophages, lymphocytes, endothelial cells, leading to the production of inflammatory cytokines (IL-1, IL-2, IL-6, tumor necrosis factor), lysosomal enzymes, and inflammatory mediators; lipid peroxidation is activated, leading to damage to the renal tissue, primarily the tubules.

The hematogenous pathway of urinary tract infection development is rare, characteristic mainly of the neonatal period in the development of septicemia and in infants, especially in the presence of immune defects. This pathway is also encountered in infections with Actinomyces spp., Brucella spp., Mycobacterium tuberculosis.

1.3 Epidemiology of the Disease or Condition

The prevalence of UTIs in childhood is about 18 cases per 1,000 children. The frequency of UTI development depends on age and sex, with children in the first year of life being affected more often. In infants and young children, UTI is the most frequent severe bacterial infection, observed in 10-15% of hospitalized patients of this age with fever. In the first year of life, UTIs are more common in boys, and at an older age, in girls. In 30% of cases, a relapsing course is observed within 6-12 months after the first episode of UTI in infants and young children [2,3].

Frequency of relapses:

- girls:

• in 30% within the 1st year after the first episode;

• in 50% within 5 years after the first episode;

- boys:

• in 15-20% within 1 year after the first episode.

1.4 Features of Coding the Disease or Condition

Acute tubulointerstitial nephritis (N10);

Chronic tubulointerstitial nephritis (N11);

N11.0 - Nonobstructive reflux-associated chronic pyelonephritis;

N11.1 - Chronic obstructive pyelonephritis;

N11.8 - Other chronic tubulointerstitial nephritides;

N11.9 - Chronic tubulointerstitial nephritis, unspecified;

N13.6 - Pyonephrosis;

N15.1 - Renal and perinephric abscess.

Cystitis (N30);

N30.0 - Acute cystitis;

N30.1 - Interstitial cystitis (chronic);

N30.2 - Other chronic cystitis;

N30.8 - Other cystitides;

N30.9 - Cystitis, unspecified;

N39.0 - Urinary tract infection of unspecified site.

1.5 Classification of the disease or condition

1. Based on the presence of structural urinary tract anomalies:

• uncomplicated - without structural urinary tract anomalies;

• complicated - in the presence of structural urinary tract anomalies (typically accompanied by fever and, as a rule, pyelonephritis).

2. By localization:

• pyelonephritis (involving the renal parenchyma and pelvis);

• cystitis (involving the bladder);

• urethritis;

• urosepsis;

• urinary tract infection of unspecified site.

3. By stage:

• active stage;

• remission stage.

4. By course:

• acute pyelonephritis

• chronic pyelonephritis (extremely rare).

1.6 Clinical presentation of the disease or condition

In the neonatal period, manifestations are generally nonspecific. Newborns may exhibit signs of a systemic inflammatory response, such as body temperature instability (periodic spikes to febrile levels)/hypotension, peripheral circulatory disorders, lethargy, irritability, apnea, dehydration, chills, seizures, or metabolic acidosis. Anorexia, poor feeding, and vomiting may also be observed. Foul-smelling urine is a rare but specific symptom of UTI. Newborns with a UTI have a high probability of bacteremia. This may lead to sepsis and, although extremely rarely, septic shock.

UTI symptoms remain nonspecific in infants under one year of age. Unexplained fever or fever without a localizing source is the most common manifestation in children during their first two years of life. In fact, it may be the only symptom of a UTI.

Overall, a UTI (specifically pyelonephritis) is more likely to be suspected in infants with a temperature ≥39°C than in children with a temperature <39°C.

Other nonspecific manifestations include irritability, decreased/absent appetite, vomiting, and abdominal pain. Specific symptoms and signs include an increase or decrease in the number of wet diapers, foul-smelling urine, and distress during urination.

A weak or dribbling urinary stream indicates a neurogenic bladder or lower urinary tract obstruction, such as posterior urethral valves in males. Continuous urine dribbling or wet diapers may indicate an ectopic ureter predisposing to UTI.

After the second year of life, symptoms and signs of UTI become more specific. Manifestations of pyelonephritis include fever (less frequently low-grade fever) without catarrhal symptoms, chills, vomiting, malaise, flank pain, back pain, and costovertebral angle tenderness.

Symptoms and signs of lower urinary tract infection include suprapubic pain, abdominal pain, frequent and/or painful urination, urinary urgency, daytime incontinence, newly onset enuresis, cloudy urine, and foul-smelling urine.

Urethritis without cystitis may present as dysuria without frequent urination or urinary urgency.

Physical examination may reveal:

• skin pallor;

• tachycardia;

• signs of dehydration (primarily in newborns and infants), absence of catarrhal symptoms in the presence of fever (more often febrile, less often low-grade);

• in acute pyelonephritis, tenderness upon percussion or, in young children, upon palpation with a finger between the 12th rib and the spine.

2. Diagnostics, medical indications and contraindications for diagnostic methods

To verify a UTI diagnosis, it is first necessary to confirm leukocyturia and diagnostically significant bacteriuria.

Next, depending on the clinical manifestations and examination results (complete blood count with differential, general biochemical blood test), a differential diagnosis between lower and upper (pyelonephritis) urinary tract infections must be performed.

2.1 Complaints and Anamnesis

See Section 1.6 "Clinical Presentation".

2.2 Physical Examination

Physical examination should focus on the symptoms described in Section 1.6 "Clinical Presentation", and blood pressure must be measured in the peripheral arteries.

2.3 Laboratory Diagnostics

• As a diagnostic method, it is recommended to perform a urinalysis (complete urine test) determining urine specific gravity, leukocyte and erythrocyte counts, as well as protein and nitrites (urine nitrite test), including the use of test strips [2,4,5,6,7,8].

(Level of Recommendations C, Level of Evidence 5)

Comments:

A urinalysis (complete urine test) is mandatory to confirm leukocyturia. Leukocyturia is defined as the detection of more than 10 leukocytes per high-power field or more than 25 leukocytes per µL of urine in a spontaneously voided urine sample.

It should be remembered that nitrites are not produced by all microorganisms causing urinary system infections; therefore, the absence of nitrites does not rule out a UTI [40]. Conversely, the presence of nitrites without leukocyturia is not indicative of a UTI.

Proper urine collection is required for accurate interpretation of test results.

Urine can be collected using the following methods:

— midstream catch of spontaneously voided urine in toilet-trained children and adolescents;

— use of urine collection bags in newborns and young children after prior hygienic preparation of the genitalia and perineum;

— bladder catheterization, performed primarily in severely ill young children when urgent UTI diagnosis is required, including for dynamic monitoring if necessary (including in patients with neurogenic bladder and other voiding dysfunctions) [41];

— suprapubic aspiration, most commonly used in severely ill young boys [8].

A positive chemical test using nitrite test strips (nitrite test) indicates a high probability of UTI; however, the high likelihood of frequent (up to 30%) false-negative results should be taken into account.

In children presenting with fever without upper respiratory tract infection symptoms, a urinalysis (complete urine test) is indicated.

Subsequently, during follow-up, it is recommended to perform a urinalysis (complete urine test) with a frequency of once a month for 3 months, then once every 3 months for a year (routinely), and non-routinely with each episode of fever and/or development of dysuria and other symptoms of urinary tract involvement.

(Level of Recommendations C, Level of Evidence 5)

Comment: Diagnostically significant is the presence of more than 100,000 colony-forming units (CFU) per mL in a midstream urine sample or 50,000 CFU per mL in a catheterized urine sample. For urine collected via suprapubic aspiration, any bacterial growth is considered significant [2,4,5,6,7,9,10].

The susceptibility testing method is selected by the microbiologist [7].

Empiric antibacterial therapy should be initiated without waiting for test results (see Section 3.1). The inability to perform a bacteriological examination (microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms) should not be a reason to delay the initiation of empiric antibacterial therapy.

(Level of Recommendations C, Level of Evidence 5)

Comment: Isolated bacteriuria in children of all ages or a positive nitrite test in the absence of leukocyturia cannot be considered signs of a urinary tract infection, as these indicators are not reliable markers of this pathology at this age. Asymptomatic bacteriuria, in most cases, is not an indication for monitoring with urine bacteriological examination (microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms) (urine culture) [42].

At the same time, in some cases, a negative result of a microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms (urine culture) with a low colony count may indicate an early infection. Therefore, if the child continues to have complaints and clinical manifestations of UTI, a follow-up complete blood count or urinalysis, or, if a UTI is diagnosed, empirical treatment is necessary, [40].

Also, in isolated bacteriuria in patients with voiding dysfunction (including patients with neurogenic bladder), additional dynamic follow-up microbiological (culture) testing of urine for aerobic and facultatively anaerobic opportunistic microorganisms (urine culture) is performed as needed [41].

(Level of Recommendations C, Level of Evidence 5)

Comments: the test may be performed if clinically indicated and during dynamic monitoring.

• In children with complicated forms of UTI, pyelonephritis, as well as in patients with pronounced ultrasound abnormalities (ultrasonography of the kidneys, ultrasonography of the urinary bladder), during a UTI exacerbation in a recurrent course, in case of using medications with nephrotoxic potential (e.g., aminoglycosides or polymyxins), it is recommended to assess renal function (blood urea nitrogen, serum creatinine, serum electrolytes [blood sodium, blood potassium, blood chloride]), calculate the glomerular filtration rate (GFR) (creatinine clearance renal function test [Rehberg test]¹), and, if necessary, uric acid [2,3,4,5,6,7,9,12].

Recommendation Strength Grade C, Evidence Reliability Level 3

Comments: ¹To assess the nitrogen-excreting renal function (creatinine clearance / glomerular filtration rate), calculation formulas should be used, giving preference to the Schwartz formula in children; additionally, serum cystatin C testing may be performed (for details, see the clinical guidelines for chronic kidney disease in the pediatric age group – services not listed in the Nomenclature of Medical Services).

Recommendation Strength Grade C, Evidence Reliability Level 3

Comments: if leukocyturia is confirmed in a febrile child, there is no need to determine CRP and PCT to confirm UTI.

complete blood count findings: leukocytosis > 15×10⁹/L; high levels of C-reactive protein (CRP) (≥30 mg/L) indicate a high probability of bacterial infection. CRP has lower specificity compared to procalcitonin.

A procalcitonin level > 1 ng/mL may indicate acute pyelonephritis in the context of a UTI and is practically absent in lower urinary tract infections.

Blood procalcitonin testing is costly and is appropriate as part of comprehensive diagnostic measures when urosepsis is suspected or when it is necessary to evaluate the response to antibiotic therapy in severe pyelonephritis [2,3,13].

Differential diagnostic signs of acute cystitis and acute pyelonephritis are presented in Table 1.

Table 1. Differential diagnostic features of acute cystitis and acute pyelonephritis [14] (as amended).

2.4 Instrumental Diagnostics

(Level of Recommendations C, Level of Evidence 5)

Comment: Ultrasound is the most accessible method, allowing for the detection of suspected structural anomalies of the urinary system (dilation of the pelvicalyceal system (PCS), ureteral stricture, etc.) and calculi.

Renal ultrasound can identify or suggest a renal abscess or perineural abscess (rare).

Ultrasound is also used to assess kidney size, general and local renal blood flow, the state of the PCS, as well as the volume and condition of the urinary bladder wall. It is advisable to perform it with a full bladder and also post-micturition.

(Level of Recommendations C, Level of Evidence 5)

Comment:

In children after the 1st episode of UTI, cystography detects grade 3–5 vesicoureteral reflux (VUR) in only 17% of cases, and grade 1–2 in 22% of children with ultrasound abnormalities [4]. VUR is detected in 25–30% of children with UTI [7].

Cystography should not be performed routinely because the procedure is invasive and involves radiation exposure.

It is not performed after the first episode of UTI except when indicated, in most cases — in children under 2 years of age.

Cystography is not performed during the active/acute stage.

Cystography may also be performed in recurrent UTIs.

Cystography for the detection of VUR, including low-grade VUR, may be omitted if renal and urinary tract scintigraphy with functional tests (dynamic nephroscintigraphy) with a micturition test can be performed in children who can control the urination process (Renal and urinary tract scintigraphy with functional tests) [2,3,4,5,6,9,16].

The procedure is performed in accordance with the consensus document (in compliance with SNMMI/EANM standards) – [43]

(Level of Recommendations C, Level of Evidence 5)

Comments: Renal and urinary tract scintigraphy (static nephroscintigraphy) is performed for:

• Recurrent UTIs in the presence of urinary system anomalies, including VUR (once every 1–1.5 years)

• Recurrent UTIs without structural anomalies of the urinary system (once every 1–1.5 years)

In recent years, magnetic resonance urography has gained greater interest due to the absence of radiation exposure (see below).

• Intravenous urography and magnetic resonance urography (MR urography) are recommended as auxiliary methods to detect urinary tract obstruction and congenital anomalies of the urinary system (after ruling out VUR) [2,3,4,5,10].

(Level of Recommendations C, Level of Evidence 5)

Comments: MR urography has certain advantages over static nephroscintigraphy (renal and urinary tract scintigraphy): it is non-invasive (no need to administer a radiopharmaceutical intravenously), involves no radiation exposure, does not take much time (the scan usually lasts 20 minutes), and allows differentiation of acute inflammation foci from fibrotic foci (which may be misinterpreted as scars on static nephroscintigraphy (renal and urinary tract scintigraphy)) [7]. However, the technique requires anesthesia in some patients and necessitates the availability of an MRI scanner and MRI-compatible anesthesia equipment.

Anesthetic management (including early postoperative care) – as clinically indicated.

Computed tomography of the kidneys and adrenal glands is used to detect focal inflammatory defects (e.g., renal abscess). Due to the high radiation dose and the risk of motion artifacts from the child, it is not performed routinely. Renal function assessment is mandatory (calculation of the glomerular filtration rate (GFR) (Nephron function study by creatinine clearance (Rehberg's test¹)

Comment: ¹the glomerular filtration rate in children should be calculated using formulas, with a preference for the Schwartz formula.

Recommendation Strength Grade C, Evidence Reliability Level 3

2.5 Other Procedures

Not required.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

(Level of Recommendations C, Level of Evidence 5)

Comment:

Table 2. Empirical antibacterial therapy for community-acquired UTIs in children.

¹ Contraindication: premature infants up to and including 41 weeks of postmenstrual age (combined gestational and chronological age); term newborns (≤28 days of age).

² Age restrictions apply depending on the route of administration.

³ Contraindicated in newborns (under 1 month), including premature infants (due to the high risk of ototoxic and nephrotoxic effects).

⁴ Oral antimicrobials may be used following parenteral administration (step-down therapy).

• When prescribing antimicrobials, it is recommended to be guided by regional uropathogen susceptibility data in order to select the most effective therapy [2,3,5,17].

(Level of Recommendations C, Level of Evidence 5)

Recommendation Strength Grade C, Evidence Reliability Level 3

Comment: Thorough genital hygiene should also be maintained. Hygienic measures must be continued after the acute UTI episode resolves.

(Level of Recommendations C, Level of Evidence 5)

Comments: performed during remission.

(Level of Recommendations C, Level of Evidence 5)

Comment: in the presence of constipation and other conditions contributing to the onset or recurrence of UTI, treatment should be carried out according to the relevant guidelines.

(Level of Recommendations C, Level of Evidence 5)

Comment: Table 3 presents doses of medications for children with UTIs and normal renal function.

Table 3. Oral antimicrobial dosing in children with UTIs and normal renal function (GFR 90 mL/min).

• In hospitalized patients, especially infants who have difficulty taking and absorbing the drug orally, antibiotic therapy is typically recommended to be initiated via the parenteral (primarily intravenous) route for the first 24-72 hours (Table 2), followed by a switch to oral administration. In the absence of severe intoxication and if the child is able to tolerate oral medication, prescribing oral antimicrobial agents from the first day is recommended [2,3,4,5,17].

(Level of Recommendations C, Level of Evidence 5)

Comments: Table 4 outlines the main and most common regimens for sequential antibiotic therapy; treatment may be adjusted according to individual indications.

Table 4. Main options for sequential antibiotic therapy¹.

Note: when switching from parenteral administration of other antimicrobial agents to oral administration, the results of microbiological testing and susceptibility testing should be taken into account; for the choice and doses of oral antimicrobial agents, see Table 3.

• For acute pyelonephritis, it is recommended that the duration of antibacterial therapy be on average at least 10 days. Longer courses offer no advantages in preventing recurrences [3,19,20].

Recommendation Strength Grade C, Evidence Reliability Level 3

Comments: shorter courses for pyelonephritis are associated with an increased risk of infection recurrence [3,44].

• In children with lower urinary tract infections (cystitis, urethritis, afebrile UTI), it is recommended to administer antimicrobial agents for 5-7 days (the exception is a single dose of fosfomycin** for acute cystitis). This duration is sufficient in most cases [2,3,4,5,18].

(Level of recommendation C, Level of evidence 5

Recommendation Strength Grade C, Evidence Reliability Level 3

(Level of Recommendations C, Level of Evidence 5)

Comments: for management of infection stones, see clinical guidelines for urolithiasis in children. Antibiotic therapy may also be considered in diabetes and pregnancy.

• Taking into account the high prevalence of resistant pathogens in the hospital environment, all patients with nosocomial UTIs are recommended to undergo microbiological (culture) urine testing for aerobic and facultatively anaerobic opportunistic microorganisms with antimicrobial susceptibility testing, followed by adjustment of empirical antibiotic therapy, especially in case of its ineffectiveness (Tables 5, 6) [3].

(Level of recommendation C, Level of evidence 5)

Comment: the test should preferably be performed before prescribing antibiotic therapy.

The empirical choice of antibiotic therapy is based on data regarding the prevalence of specific nosocomial pathogens in a particular department/hospital and local data on their susceptibility to antimicrobial agents.

Dosages for patients with renal impairment are adjusted in accordance with the instructions. Doses of parenteral antimicrobial agents for UTIs in children with normal renal function are presented in Table 7.

Table 5. Empirical antibacterial therapy for nosocomial UTIs in children [21,22,23]

¹ in severe cases

Table 6. Recommendations for targeted antibiotic therapy of nosocomial UTIs in children^1. [23,24,25,26,28,29,30]

¹ in any case, the choice of antimicrobial agents should be based on the susceptibility testing results of the isolated pathogen

² in severe cases

Table 7. Dosage of parenteral antimicrobial agents for UTI in children with normal renal function¹. [21,22,23,25,26,28,30,31,32]

¹ - switching from parenteral to oral therapy with the same drug / or an antimicrobial of the same class is possible upon clinical improvement

² - sources - [45]

³ - source - [46]

3.2 Surgical Treatment

Not required for the treatment of acute UTI.

May be necessary for underlying conditions/diseases causing UTI (according to established approaches to the management of relevant urological pathology).

3.3 Other Treatment

Complementary and alternative medicine (CAM) methods in the treatment of UTI.

CAM methods combine various therapeutic approaches not fully based on conventional medical principles. At the same time, CAM is grounded in real-world evidence from scientifically sound clinical practice and, in some cases, reliable results meeting conventional efficacy and safety criteria. Thus, evidence supporting the use of specific CAM methods for various diseases includes outcomes superior to placebo and comparable to standard treatment approaches [47,48].

Thus, CAM methods used as an adjunct to core recommendations can improve patient and parental compliance and collaboration with the healthcare provider in achieving disease control, optimizing the patient's environment during prolonged courses of conventional treatment until complete recovery. Alternative/complementary treatment does not replace conventional treatment, including antibiotic therapy, yet it may help reduce the risks of systemic antimicrobial overuse and improve patient/legal representative compliance [50,51,52].

When deciding on complementary treatment, potential benefits and risks must be weighed, including ruling out allergic reactions (e.g., to herbal components) and accounting for specific disease features (e.g., ascorbic acid** should not be prescribed in oxaluria).

Recommendation Strength Grade C, Evidence Reliability Level 3

Comments: the combination of centaury herb + lovage root + rosemary leaves can be prescribed to children over 6 years of age in age-appropriate dosage (as drops or tablets) for a 2-4 week course, provided there is no sensitivity to plants of the Apiaceae (Umbelliferae) family (including anise and fennel) or to anethole (a component of essential oils from plants such as anise and fennel).

(Level of Recommendations C, Level of Evidence 5)

Comments: the combination of centaury herb + lovage root + rosemary leaves can be prescribed to children older than 6 years in age-appropriate dosages (tablets), and from 1 year of age in the form of drops, either during the acute period as an adjunct to antibacterial therapy or after resolution of symptoms for a 2-4 week course, provided there is no sensitivity to plants of the Apiaceae family (including anise and fennel) or to anethole (a component of essential oils from plants such as anise and fennel).

(Grade of Recommendation: B; Level of Evidence: 1)

(Grade of Recommendation: C; Level of Evidence: 4)

Comments: there are reports of a positive effect from this intervention, but further studies are needed.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not required.

5. Prevention and Dispensary Observation

• All children as part of primary prevention are recommended to:

- Regular emptying of the bladder and bowel

- Adequate fluid intake (in a physiological volume)

- Hygiene of the external genitalia [33,34,35,36].

(Level of Recommendations C, Level of Evidence 5)

• Currently, prophylactic administration of antibiotics to prevent UTI recurrences is not recommended in most cases due to unproven clinical utility. [3,37,38].

(Recommendation grade B, level of evidence 1)

Comment: According to several studies, long-term antibiotic use may reduce the risk of recurrent symptomatic UTIs in children, but the benefit is small. Antibiotic prophylaxis does not prevent the formation of new renal parenchymal scars. In most cases, long-term antimicrobial prophylaxis for UTIs is not recommended, partly due to the increasing antibiotic resistance of uropathogens.

Nevertheless, such regimens (Co-trimoxazole [Sulfamethoxazole + Trimethoprim]**) may be considered for children under 1 year of age with frequently recurring UTIs and urinary tract structural anomalies [68,69].

• All children in their 1st year of life are recommended to undergo ultrasound examination of the kidneys and bladder as part of routine health screening for early detection of renal and urinary tract developmental anomalies [11].

(Level of Recommendations C, Level of Evidence 5)

Dispensary monitoring (active follow-up)

(Level of Recommendations C, Level of Evidence 5)

Comments:

Follow-up for patients who have had acute pyelonephritis should be carried out for at least 3 years, and for acute cystitis – for at least 1 year.

During this period, routine urinalysis should be performed in children after acute pyelonephritis with a frequency of once every 1–3 months, then once every 3 months for a year, and thereafter – in case of fever and/or dysuria and other symptoms of urinary tract involvement.

For children with cystitis – routine urinalysis is not required in most cases; it is performed only in the presence of symptoms and in children with voiding dysfunction

Microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms with susceptibility testing to antimicrobial chemotherapeutic agents (urine culture) is performed when leukocyturia appears and/or during unmotivated temperature spikes without catarrhal symptoms.

A complete blood count (CBC) is performed based on clinical necessity during follow-up.

Monitoring of proteinuria (as a factor of renal injury in recurrent pyelonephritis) – as part of the routine urinalysis.

Assessment of renal functions – concentration and filtration – in case of a recurrent UTI course (determination of blood creatinine level and calculation of GFR, if necessary – blood cystatin C test – with determination of CKD stage – see clinical guidelines for chronic kidney disease (age category - children) – once a year.

Ultrasound examination of the kidneys and ultrasound examination of the bladder – once a year. In case of recurrent UTIs – at each recurrence, then during remission according to the planned dispensary follow-up schedule.

Repeat instrumental examinations are performed with the following frequency:

- cystography – once every 1–2 years in recurrent pyelonephritis with frequent exacerbations and diagnosed VUR;

- static renal scintigraphy (Scintigraphy of the kidneys and urinary system) in recurrent UTIs associated with VUR – once every 1–1.5 years, in recurrent UTIs without structural urinary tract anomalies – once every 1–1.5 years.

Monitoring the severity of urodynamic disturbances over time (obstructive uropathy, VUR) (see subsection "Instrumental Diagnostics") if present, and timely referral for surgical correction if necessary.

Blood pressure monitoring in urinary tract developmental anomalies and recurrent pyelonephritis (at each doctor's visit, if necessary – upon doctor's recommendation – monitoring at home daily or upon appearance of complaints (headache, weakness, etc.).

Monitoring the effectiveness of therapeutic and preventive measures and their adjustment if necessary (depending on clinical manifestations, and the need to perform and evaluate the results of laboratory and/or instrumental examinations).

Vaccination within the National Immunization Schedule during UTI remission [Order of the Russian Ministry of Health No. 1122n dated December 6, 2021 "On approval of the national schedule of preventive vaccinations and the schedule of preventive vaccinations for epidemiological indications", Methodological Guidelines MU 3.3.1.1095-02. Medical contraindications to preventive vaccinations with national immunization schedule preparations].

(Level of Recommendations C, Level of Evidence 5)

Comment: The use of glucocorticoid creams used in dermatology for physiological phimosis in boys with UTIs statistically significantly reduces the rate of UTI recurrences [39].

6. Organization of Medical Care

Medical care for children with UTIs can be provided on an outpatient basis, in a day care setting, or in an inpatient setting.

The patient is managed by a nephrologist, pediatrician, or general practitioner (family doctor); consultations and examinations involving a pediatric urologist-andrologist, obstetrician-gynecologist, geneticist, clinical pharmacologist, pediatric surgeon, and others are carried out as needed.

If necessary, hospitalization is usually carried out in a nephrology or pediatric department.

6.1 Indications for hospital admission to a medical organization

1. Children under 6 months of age with febrile fever;

2. Children with acute pyelonephritis presenting with symptoms of intoxication and vomiting;

3. Inability to perform oral rehydration in the presence of signs of dehydration;

4. Bacteremia and sepsis;

5. Acute urinary retention.

The length of hospital stay for UTIs is no more than 10-14 days. In the absence of these indications, medical care for children with urinary tract infections can be provided in an outpatient setting or a specialized day hospital setting.

6.2 Indications for discharge from a medical organization

1. Absence of fever;

2. Absence of symptoms of intoxication;

3. Normalization of urine analysis.

7. Additional Information

7.1 Complications

1. Bacteremia develops rarely (in 5.6% of UTI cases); risk factors for bacteremia may also include prematurity and early age (first year of life). Urosepsis can also develop with inadequate treatment of pyelonephritis.

2. In a recurrent course and/or development of UTIs against the background of VUR, there is a high risk of reflux nephropathy.

[7]:

In acute pyelonephritis, electrolyte disorders and acid-base balance disturbances may develop. Acute kidney injury can develop both as a result of the severe course of pyelonephritis itself (often as a result of its occurrence against the background of a severe renal developmental anomaly) and as a result of the nephrotoxic effect of administered antibiotics, as well as active antipyretic therapy. With the progression of renal damage due to repeated attacks of pyelonephritis, a significant reduction in the volume of functioning parenchyma and the development of chronic renal failure up to the end-stage requiring renal replacement therapy are possible. Such UTI complications as abscess, pyonephrosis, emphysematous pyelonephritis, and xanthogranulomatous pyelonephritis are currently (in the antibacterial era) extremely rare.

7.2 Outcomes and Prognosis

The overwhelming majority of acute UTI cases end in recovery.

Focal renal parenchymal damage develops in 5% of girls and 13% of boys after the first episode of febrile UTI; overall, it is detected in 10-20% of patients who have had pyelonephritis, and the predominant triggering factors, along with infection recurrences, are high-grade VUR, obstructive uropathies, and hypodysplasia (of one or both kidneys), late initiation of antibiotic therapy, as well as bacterial virulence and individual susceptibility.

During the first two years of a child's life, the kidneys are most vulnerable to damaging action with the development of scarring; this risk decreases by about eight years of age, after which it significantly declines. When VUR is detected at an early age (less than 2 years), renal scars are detected after 5 years in 24% of cases, and in older children – in 13% of cases. Thus, more active diagnosis and treatment at an early age reduce the risk of progression to the stage of chronic renal failure.

Arterial hypertension develops in approximately 25% of children with reflux nephropathy.

UTIs impair the quality of life of the child and their parents, as well as the routine of the entire family, especially in cases of recurrent UTIs or irreversible renal damage.

UTI in infancy is a risk factor for recurrent abdominal pain in childhood.

Criteria for Evaluating the Quality of Medical Care

Table 1. Quality of care criteria for primary health care delivery to children with urinary tract infection (ICD-10 codes: N10, N11, N13.6, N30.0, N30.1, N39.0).

Table 2. Quality of care criteria for specialized medical care delivery to children with urinary tract infection (ICD-10 codes: N10, N11, N13.6, N30.0, N30.1, N39.0).

References

Appendix A1. Working Group Composition

Baranov A.A., Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Chief Freelance Pediatrician of the Russian Ministry of Health

Kozlov R.S., Corresponding Member of the RAS, Professor, MD, Rector of the Smolensk State Medical University of the Ministry of Health of Russia, Chief freelance specialist of the Ministry of Health of Russia in Clinical Microbiology and Antimicrobial Resistance, President of ISCMR

Namazova-Baranova L.S., Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Preventive Pediatrics of the Russian Ministry of Health

Andreeva I.V., Head of the Clinical Guideline Development Department, Associate Professor, Research Institute of Antimicrobial Chemotherapy of the Smolensk State Medical University of the Russian Ministry of Health, Member of MACMAH

Vishnyova E.A., Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Zokirov N.Z., Doctor of Medical Sciences, Head of the Department at the Academy of Postgraduate Education of the Federal Medical and Biological Agency, Federal Research and Clinical Center of Children and Adolescents of the FMBA, Member of the Union of Pediatricians of Russia.

Kulichenko T.V., Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Pirogov Russian National Research Medical University of the Russian Ministry of Health, World Health Organization Expert, Member of the Union of Pediatricians of Russia

Margieva T.V., Candidate of Medical Sciences, Chief Specialist of the Methodological Center for Specialist Accreditation at Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Nephrologist, Member of the Union of Pediatricians of Russia

Dovgan E.V., Head of the Clinical Pharmacology Department at the Smolensk Regional Clinical Hospital, Member of MACMAH

Stetsyuk O.U., Senior Researcher, Research Institute of Antimicrobial Chemotherapy of the Smolensk State Medical University of the Russian Ministry of Health, Member of MACMAH

Tatochenko V.K., Doctor of Medical Sciences, Professor, Advisor to the Director of the National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Chumakova O.V., Professor, Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia

Shilova M.M., Candidate of Medical Sciences, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health

Emirova Kh.M., Candidate of Medical Sciences, Professor at the Department of Pediatrics, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, St. Vladimir City Children's Clinical Hospital, Member of TODN, RDO

Tsygin A.N., Professor, Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document). Doctor of Medical Sciences, Professor, Head of the Nephrology Department at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor at the Department of Nephrology, N.A. Semashko Scientific Research Institute of Clinical Medicine, Russian University of Medicine of the Russian Ministry of Health, President of the Creative Association of Pediatric Nephrologists

Shishimorov I.N., Doctor of Medical Sciences, Head of the Department of Pediatrics and Neonatology, Institute of Continuing Medical and Pharmaceutical Education, Volgograd State Medical University of the Russian Ministry of Health, President of the Volgograd Regional Branch of the Union of Pediatricians of Russia;

Shaposhnikova N.F., Candidate of Medical Sciences, Associate Professor at the Department of Pediatrics and Neonatology, Institute of Continuing Medical and Pharmaceutical Education, Volgograd State Medical University of the Russian Ministry of Health

Sergeeva T.V., Professor, Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Paunova S.S., Professor, Doctor of Medical Sciences (participation in the original version of the document).

Komarova O.V., Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Bakradze M.D., Professor, Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Tsygina E.N., Professor, Doctor of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Zrobok O.I., Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Vashurina T.V., Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Lupan I.N., Candidate of Medical Sciences (participation in the original version of the document).

Kagan M.Yu., Candidate of Medical Sciences (participation in the original version of the document).

Matveeva M.V., Candidate of Medical Sciences (participation in the original version of the document).

Chashchina I.L., Member of the Union of Pediatricians of Russia (participation in the original version of the document).

Polyakova A.S., Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia.

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric urologists-andrologists;

2. Pediatricians;

3. General practitioners (family physicians);

4. Nephrologists;

5. Medical students;

6. Residents and postgraduate students.

Methods used for evidence collection/selection:

- searching electronic databases.

Methods used for analyzing evidence:

- reviews of published meta-analyses;

- systematic reviews with evidence tables.

Methods used to formulate the recommendations:

- Expert consensus;

- Significance assessment according to the grading scheme.

The strength and quality of the recommendations according to the evidence analysis (Tables P1, P2) are provided in the text.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions).

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions).

Table 3. Scale for grading the levels of evidence (LE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Procedure for Providing Pediatric Care".

2. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of the Criteria for Assessing the Quality of Medical Care".

3. Information on medicinal products: State Register of Medicines: https://grls.rosminzdrav.ru

4. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724).

5. International Classification of Diseases, Injuries and Causes of Death (ICD-10).

6. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012 "On approval of the nomenclature of positions of medical and pharmaceutical workers".

7. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

8. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

9. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

10. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

11. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates, Procedure for Issuing Said Forms, Their Accounting and Storage."

12. Medical contraindications to preventive vaccination with vaccines of the national immunization schedule: Guidelines.—M.: Federal Center for State Sanitary and Epidemiological Surveillance of the Russian Ministry of Health, 2002.— 16 p.

13. "Guidelines for the Detection, Investigation and Prevention of Adverse Events Following Immunization" (approved by the Russian Ministry of Health on April 12, 2019).

Diagnosis examples:

• Acute pyelonephritis, active stage. Renal function preserved.

• Urinary tract infection, 1st episode, active stage. Renal function preserved.

• Urinary tract infection, recurrent course, active stage. Renal function preserved.

• Reflux nephropathy. Secondary chronic pyelonephritis. Remission stage. Chronic kidney disease, stage 1.

• Acute cystitis, active stage. Renal function preserved.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

The urinary system consists of the kidneys, ureters, urinary bladder, and urethra. The urinary system serves for the formation, storage, and elimination of urine from the body.

Urinary system infections (urinary tract infections: pyelonephritis, cystitis) are caused by bacteria.

Children most susceptible to urinary tract infections are those with:

• Anomalies of the urinary system development

• Bladder dysfunction

• Boys with phimosis.

Signs that may be observed in children with a urinary tract infection:

In a child under 2 years of age, the clinical picture may be non-specific:

• High body temperature without other apparent causes;

• Vomiting and diarrhea;

• Loss of appetite;

• Crying.

In a child older than 2 years:

• High body temperature without other apparent causes

• Frequent and/or painful urination;

• Back or flank pain.

If a urinary tract infection is suspected, consult a pediatrician (or nephrologist).

The doctor prescribes a urinalysis. Please note that the urine sample must be collected exactly as directed by the physician.

Urinary tract infections are treated with antibiotics. It is extremely critical to follow the regimen and duration of treatment prescribed by the doctor. Prematurely discontinued treatment will not be effective.

If a child has recurrent urinary tract infections, a more in-depth evaluation prescribed by a nephrologist may be required.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Scales, questionnaires, and other assessment tools are not used.