Cystitis in Children

Abstract

Urinary tract infections in children are very common. However, their etiology, treatment, and prognosis are very different compared to adult patients. It is a field of interest that is covered by Pediatricians, Pediatric Nephrologists, Pediatric Surgeons, and Pediatric Urologists. There are of course different approaches with a common goal of urinary tract treatment, prevention, and in more serious cases kidney function preservation. This chapter offers a comprehensive review on the topic, with an attempt to offer impartial analysis of the practices widely accepted in treatment of urinary tract infections in childhood, with all the specific procedures typical for pediatric population.

1. Introduction

Cystitis represents a condition in which there is an inflammation of the bladder mucosa, caused by different factors [1]. Modern medical literature is mostly based on cystitis of an infectious etiology, due to its significant frequency in both general and pediatric populations [2, 3]. Nevertheless, it would be wrong to disregard the fact that some forms of cystitis in children could be of non-infectious etiology. They can be acute or chronic, and their clinical manifestations can vary from asymptomatic forms to life-threatening ones [4]. Due to its frequency and a tendency for recurrence, cystitis represents a significant health problem in childhood [1, 2].

Following a large number of publications about cystitis in adults, there has been increasing interest in cystitis in the pediatric population taking into account various causes, as well as the possibility of negative long-term renal consequences and quality of patients’ life.

We searched for the available literature to identify studies and reviews relevant to the scope of this review. Considering different epidemiologic aspects of urinary bladder infections, this chapter also represents a summary of international guidelines from pediatric and pediatric urologic societies.

2. Classification and pathogenesis

There are several necessary factors for the development of infectious cystitis: breakthrough of the pathogenic microorganisms into the bladder, as well as their growth and reproduction. As a part of a lower urinary tract infection (LUTI), the bladder is inflamed together with the urethra, but sometimes the entire urinary system is affected irrespective of the point of origin of the infection [2].

The newest classifications of cystitis take into account the clinical presentation and risk factors and are accordingly classified into symptomatic and asymptomatic, i.e. complicated and uncomplicated cystitis [1]. Symptomatic cystitis represents a condition with clearly present symptoms related to the lower urinary tract. Asymptomatic bacteriuria represents the finding of significant bacteriuria in a child without lower urinary tract symptoms (LUTS). There are a significant number of non-virulent strains of bacteria that do not cause a response activation of the organism. In children with neurogenic bladder, it is sometimes difficult to differentiate between the symptomatic and asymptomatic forms of cystitis [1, 5].

Uncomplicated cystitis develops in children with normal morphologic and functional characteristics of the urinary system, while complicated cystitis is defined as an inflammation of the bladder mucosa in children with already present disorders of the urinary system, or associated diseases [5].

3. Epidemiology

The exact incidence of cystitis in children is not determined, as most of the published data in modern literature refer to overall UTI in the pediatric population [3]. Incidence depends on the gender as well as the age of the child. UTI are more common in males only in the newborn period, most likely due to the greater incidence of congenital urinary tract malformations in boys. In children up to two years of age, there is a strong tendency for the infection to spread over the entire urinary system in a very short period. Cystitis then develops as a part of the infection of the entire urinary system, with non-specific clinical presentation. Therefore, cystitis in children often goes unrecognized [3, 5, 6]. From the second year onwards, the incidence of cystitis and UTI, in general, are more common in girls [2]. School-aged girls have a UTI incidence of 1–3%, and with the start of sexual activity, it rises up to 10% [3, 7, 8]. Asymptomatic bacteriuria is more common in school-aged girls [3%] and male newborns (1%) [5].

In the first 6–12 months after the first UTI, approximately 30% of children have a recurrent UTI of different localization. If a recurrence appears, there are several risk factors that need to be evaluated with additional diagnostic procedures [2, 5].

4. Etiology

Different microorganisms can cause cystitis. They are usually an integral part of the normal bowel flora. Less commonly, microorganisms invade the urinary tract system from the environment during different diagnostic and therapeutic procedures [9, 10].

The most common microorganisms causing cystitis in children are gram-negative bacteria from the family of Enterobacteriaceae. Escherichia coli is the normal inhabitant of the bowel flora and it is a cause of up to 80–90% of all cystitis [2, 10]. It is most commonly diagnosed in uncomplicated cystitis, i.e. in children without congenital malformations, stones, or inserted urinary catheters [3].

Other gram-negative bacteria (Proteus, Klebsiella, Enterobacter, and Pseudomonas) are less common causative agents of cystitis, and they play a role in recurrent infections and infections related to anatomic and functional malformations of the bladder. They are also more commonly associated with urolithiasis and nosocomial infections related to different urological interventions. It is well known that Proteus mirabilis and Klebsiella are producing urease, extracellular mucus, and polysaccharides that take part in the development of the urinary calculi, and are therefore significant causative agents associated with urolithiasis [2, 3, 10].

Gram-positive bacteria are less relevant in pediatric bladder infections. The most commonly isolated bacteria are coagulase-negative Staphylococcus saprophyticus. It is a cause of 10–15% of acute cystitis in adolescent girls [10]. Enterococcus and Staphylococcus aureus are isolated in cystitis in patients with urolithiasis, previous urological interventions, or placed urinary catheters. Ureaplasma urealyticum is sometimes diagnosed in girls in puberty [2, 10].

Besides bacteria, cystitis might be caused by other microorganisms, but far less commonly. In immunocompromised children, children with diabetes, and children with indwelling catheters colonization of the bladder with Candida and/or other fungi is not uncommon. In these cases, one must take into account the risk of the progression of cystitis into an invasive systemic infection, necessitating adequate diagnosis and treatment [2, 11, 12].

Viral cystitis is most commonly diagnosed in patients with bone marrow transplantation. The most common causative agents are viruses from the polyoma group (BK virus, JC virus, and cytomegalovirus) [13]. Adenovirus can cause epidemic hemorrhagic cystitis in the pediatric population without comorbidities [10].

Infection of the bladder with mycobacteria tuberculosis is a rare, but very serious infection. Unrecognized and inadequately treated, it can have severe complications, such as urinary stricture and decreased bladder compliance [11].

Parasitic causes of cystitis should be suspected in children coming from endemic regions, or bad hygienic conditions. The most commonly diagnosed parasite as a cause of cystitis is Schistosomiasis haematobium [10].

There is only a little literature data on non-infectious cystitis in children. Certain medications used in pediatric oncology and pediatric immunology are known to cause chemical cystitis [4]. It is proven that cyclophosphamide use can cause Hemorrhagic Cystitis (HC). Adequate hydration as a preventive measure for the development of HC is an important part of supportive therapy in patients treated with cyclophosphamide [14] (read the chapter: “Drugs related cystitis” of this book).

The use of different soaps and baths in children can cause chemical/allergic reactions when in contact with the urethral mucosa. This reaction can spread upstream to the bladder causing inflammation of the bladder mucosa. This is more common in girls, due to a shorter urethra and consequent faster spread of inflammation [15].

In cases of cystitis caused by a non-infectious agent, urine culture is typically negative. However, sometimes the chemical agent leading to the inflammation of the bladder mucosa serves as a starting point for the colonization of the bladder with bacteria. This is an important fact to be taken into account when diagnosing and treating cystitis (Table 1).

Infectious agents
Bacterial	Gram-negative: Escherichia coli Proteus Klebsiella Enterobacter Pseudomonas Gram-positive: Staphylococcus saprophyticus Staphylococcus aureus Enterococcus Ureaplasma urealyticum Mycobacterium tuberculosis
Viral	Adenovirus; BK virus; JC virus; Cytomegalovirus
Fungi	Candida
Parasitical	Schistosomiasis haematobium
Non-infectious agents
Chemical	Medications (e.g. cyclophosphamide)
Allergic	Soap, baths

Table 1.

Etiopathogenic agents of cystitis in children.

5. Pathophysiology

The bladder is the distal part of the urinary system and is a temporary reservoir for collecting urine. The proximal part of the urethra and the bladder are generally sterile. The dominant way of a breakthrough of the microorganisms in this region is the ascending one. In children predisposed to the development of cystitis, the first region that gets colonized is the periurethral region, the vaginal introitus, and the prepuce. Due to the invasion of the microorganisms in this region, subsequently, the bladder mucosa gets inflamed. If, in certain cases, the bladder is infected after the primary infection of the kidneys and upper urinary tract, we refer to that kind of infection as descendent [2, 9, 16].

Many factors enable the development of cystitis, and they represent a good example of interaction between the host and the microorganism. For the development of the infection of the bladder mucosa, the virulence of the microorganism is as important as the sensitivity of the host and its defense mechanisms [16].

The most studied is the virulence of Escherichia coli as the most common cause of cystitis. The most important factor determining the virulence of E. coli is the existence of the so-called fimbriae—filamentous organelles (P-fimbriae). They enable the bacteria to get attached to the uroepithelium and prevent its flushing with the stream of urine. At the same time, they enable its ascent towards the upper parts of the urinary system. Thanks to the recognition of the fimbria structure, as well as the structure and mechanism of action of the receptors on the urothelium for P-fimbriae and their mechanism of interaction, it is possible to determine in the laboratory setting the existence of this particularly virulent and pathogenic strain of E. coli. There are other factors influencing the virulence of E. coli such as endotoxin, chymolysine, cytotoxic necrosis factor, as well as the use of different metals (iron and zinc) for nutrition through a system of siderophores and chemoreceptors, the mobility due to flagella existence, and avoidance of the immune response of the host [2, 3, 16].

An important role in the development of cystitis is the disturbance of the general as well as local defense mechanisms of the child. Of the local ones, the most important role is that of the normal urinary hydrodynamic. If due to anatomical or functional disorders there are disturbances in the normal process of urine elimination, the residual urine decreases the normal bactericidal capacity of the uroepithelial cells leading to the fast reproduction of the bacteria [9].

The most common predisposing factors for the development of cystitis are malformations of the urinary tract, primary, and secondary vesicoureteral reflux (VUR), obstructions at different levels and different etiologies, urolithiasis, and different forms of bowel and bladder elimination syndrome [17].

Factors predisposing to the periurethral colonization and disturbance of normal periurethral flora in children, such as previous use of antibiotics for any indication [3], play a special role in the development of cystitis in children. In adolescent girls, the initiation of sexual intercourse plays an important role in the development of cystitis. The use of contraceptives causes changes in the previous vaginal microbial flora, increasing the risk of cystitis development [18].

The presence of a non-retractable prepuce in male infants is a well-documented risk factor for the development of cystitis. It has been shown that uncircumcised infants have a 10 times bigger risk of cystitis development compared to their circumcised counterparts [19].

Congenital or acquired IGA immunodeficiency also contributes to the vulnerability of the pediatric population and their predisposition towards cystitis development. Another group of pediatric populations with an increased incidence of cystitis are patients with diabetes mellitus [2, 3].

There is more and more data corroborating genetic predisposition to cystitis. An important factor in the development of urinary tract infections is the presence of specific receptors on the urothelial cells that are binding with the bacteria. The number and type of those receptors are genetically determined. Most of these structures are parts of blood group antigens that are present on erythrocytes and uroepithelial cells [20]. Genes that might be responsible for the preponderance of recurrent urinary tract infections are HSPA1B, CXCR1, CXCR2, TLR2, TLR4, and TGFbeta1 [21]. Although few significant mutations are identified to implement these data into daily clinical practice, further research is necessary [3].

6. Clinical presentation

Symptoms of cystitis in the pediatric population are different at different ages. In the first months of life, the symptoms of UTI are non-specific, and if not recognized early, they might develop into pyelonephritis and sepsis. Infants with urinary tract infections often present with lethargy, irritability, failure to thrive, and prolonged neonatal jaundice. Sometimes there are also vomiting and diarrhea. Neonate or an infant is usually febrile pointing toward an infection of the upper urinary tract and systemic infection. That is why a UTI should be suspected in every neonate or infant with an unclear cause of fever.

From the age of approximately 3–24 months, the symptoms are similar. Urine might be turbid and malodorous, and a child might be complaining of abdominal pain. After the second year, the symptoms become more specific, similar to symptoms in the adult population. Cystitis is usually manifested with dysuria, urgency, and frequency. Enuresis appears in some cases in children that have previously achieved nocturnal continence. These symptoms are often accompanied by fever up to 38°C, malodorous urine, and macroscopic hematuria [2, 11, 16].

Symptoms and signs of fungal cystitis are very similar. Besides the aforementioned symptoms, anuria might develop as a consequence of the obstruction of the urinary system due to the presence of the so-called “fungal ball” formed in the bladder.

The clinical presentation of viral cystitis essentially does not differ from the presentation of bacterial cystitis. Dysuria, macroscopic hematuria, and suprapubic pain are the most common manifestations of viral cystitis [2, 13].

Differential diagnosis in children when cystitis is suspected could be nephrolithiasis, urinary tract obstruction of different etiologies, appendicitis, gastroenteritis, parasitic bowel infections, vulvovaginitis, and balanitis. In adolescent girls that are sexually active and have cystitis with or without vaginitis, pregnancy should always be considered [22].

7. Diagnosis

Diagnosis of cystitis is based on well-taken patient history, physical examination, and laboratory testing. The patient history should include the question of first or recurrent infections, fetal abnormalities, and any malformations of the urinary tract, prior surgeries, family history, and the presence of obstipation or voiding dysfunctions. The radiologic examination is unnecessary for diagnosing cystitis but is important in the diagnostics of anatomical and functional abnormalities of the urinary tract predisposing to the development of cystitis in children.

Adequate choice of diagnostics is very important for differentiating between infections of the upper urinary tract system (pyelonephritis) and lower urinary tract infection (cystitis), which is often very challenging [23].

The physical examination should include a whole-body examination of the throat, lymph nodes, abdomen, genitalia, flank, and back. It most often reveals abdominal or suprapubic tenderness on palpation. Voiding is interrupted, the flow is weak, and there is straining and decreased voided volume, sometimes up to only a few drops of urine. Examination of the external genitalia might reveal certain anomalies, like the presence of a foreign body, vulvitis, or balanitis, or indicate a possible sexual assault [10, 16].

In acute cystitis, fever might be present, but most of the patients are subfebrile. Systemic laboratory inflammation parameters alone are not sufficient to confirm the presence of cystitis. In circumstances of the negative findings of C reactive protein, procalcitonin pyelonephritis could be excluded [24, 25].

The golden standard in diagnosing UTI, that is, cystitis is significant bacteriuria. To take this finding truly as a golden standard, sampling must be done appropriately. The choice of sampling method depends on the age of the patient, the urgency of the testing, and the need for the microbiological examination. This is particular challenge in non-toilet-trained children. Urine can be obtained with urine sampling bags in neonates and infants, by catching the middle stream of urine during voiding in older children, or in special circumstances by catheterization either suprapubically or through the urethra. Before urine sampling, adequate hygiene of the periurethral region is recommended [11, 22, 26].

A sampling of urine with urine sampling bags is used in children that have not achieved voluntary voiding. The testing of the urine collected in such a way can be only used as a screening method, and further microbiological tests of such urine are not recommended. The American Academy of Pediatrics (AAP) guideline states that bag cultures have “an unacceptably high false-positive rate and are valid only when they yield negative results,” stating that the rate of false positives ranges from 88 to 99% of tests [3, 27].

If the chemical and cytological finding of the urine is normal, UTI can be ruled out. In case of a pathological finding, it is necessary to obtain another urine sample some other way due to a high chance of contamination [28].

First-morning urine sampling should be performed in children with voluntary voiding. In toddlers that are still not fully toilet trained, a clean catch might be attempted, in which case a risk of contamination is far less than in urine collected in a sampling urine bag. In any case for the results to be evaluated adequately, the sampling method must be noted [28, 29]. Suprapubic and lumbosacral stimulation are the methods of voiding stimulation. Another alternative is the Quick-Wee method of urine collection. In this method, the suprapubic area stimulated by using a gauze soaked in cold fluid and the voided midstream urine is caught in sterile cup [3, 28].

When it is not possible to collect urine non-invasively then catheter sampling or suprapubic aspiration should be used. Catheterization of the bladder is usually performed in children younger than 3 years. It is considered a safe and reliable urine sampling method, with a low risk of introducing bacteria into the urinary system. Suprapubic aspiration is the most reliable urine sampling method in neonates and infants but is also the most invasive one. It is performed in critically ill children in a need of prompt and reliable diagnostics [28].

After adequate urine sampling, the analysis could be performed with the dipstick test and/or microscopic examination of the urine sediment, and additional microbiological analysis could be performed when needed. The main advantage of the dipstick test is the availability of prompt information that could influence further diagnostics and treatment. The most commonly used findings in a dipstick test are leukocytic esterase and nitrites. Leukocytic esterase is an enzyme produced by leucocytes that can be found in urine during an active bladder infection. Positive leucocyte esterase on a dipstick test corresponds to the finding of more than 5 leukocytes in a microscopic exam. Nitrites are a side product of bacterial metabolism in the bladder. Compared to leukocytic esterase, nitrites are less sensitive, but more specific in diagnosing cystitis. Urine that is left at room temperature for more than 1 hour is not useful, leukocyte esterase test loses sensitivity, and nitrite test loses specificity. Macroscopic or microscopic hematuria is often associated with cystitis, irrespective of positive leukocytic esterase and nitrites [1, 10, 11, 22, 30]. Sterile pyuria may occur in association with infections such as tuberculosis, fungal, viral, and parasitic. It can also occur with acute glomerulonephritis, analgesic nephropathy, appendicitis, or chemical cystitis [3, 10].

Significant bacteriuria is defined as more than 100,000 colony-forming units (CFUs)/mL if urine is collected through the clean catch of the first-morning urine. Since 2011, there has been a recommendation from the AAP that significant bacteriuria in children 2–24 months old is the finding of 50,000 colony-forming units (CFUs)/mL of urine [27]. Finding less than 10,000 colony-forming units (CFUs)/mL of urine is considered contamination. If the urine is obtained through suprapubic aspiration, the finding of any bacteria in urine is significant, and in cases of urine sampling through catheterization, the significant bacteriuria is defined as more than 10,000 colony-forming units (CFUs)/mL of urine. Multiple isolated bacteria suggest contamination of a urine sample. Also, the presence of more than 10 epithelial cells with an insignificant number of bacteria in urine culture suggests contamination. Non-uropathogenic bacteria are Lactobacillus, Staphylococcus epidermidis, and Streptococcus viridans. The growth of these bacteria in urine culture is also considered contamination. Patients with urinary frequency (i.e., decreased bladder incubation time) are those most likely to have bacteria proliferating in the urinary bladder in the presence of low colony counts, which can result in false-negative results [3, 11, 23, 31].

To confirm the diagnosis of candida cystitis, the finding of more than 10,000/ml of urine is necessary. Since most fungal urinary infections are associated with urinary tract malformations, ultrasound is a very useful diagnostic tool. It is especially useful in identifying “fungus balls” in the bladder [2, 12].

Diagnosis of viral cystitis is based upon the identification of the presence of the virus in the urine with PCR. Serologic examinations are unreliable in diagnosing viral cystitis, especially in immunocompromised children, due to an inadequate immune response in such patients [2].

An effort should be made to localize an infection and identify causative organism because some patients do not need conventional antibiotic therapy (viral and chemical cystitis, etc.) [27].

Ultrasound is not a mandatory part of the diagnostic protocol in patients with cystitis. If performed, an ultrasound usually shows thickened bladder wall. In patients with repeated cystitis, it should be done after the acute phase of infection, to avoid false-positive findings associated with edema of the bladder mucosa or dilatation of the urinary tract due to the release of endotoxins. It is, however, mandatory in cases of the suspected presence of urinary tract anomalies, the presence of obstruction, or in cases of recurrent cystitis of unclear etiology [3, 9].

Whatever, in order to make the correct diagnosis of cystitis and make a good decision, it is very important to take into account all the mentioned diagnostic criteria. Taking these parameters in combination can improve the sensitivity and specificity compared with testing each in isolation.

8. Treatment

The treatment of cystitis aims to remove the causative agent of the bladder inflammation and prevent further breakthroughs of the infection, and its recurrence.

Children with cystitis are usually treated ambulatory. In cases of dehydration, intolerance of oral intake, or urinary tract obstruction, it is necessary to admit the patient. Absolute indication for admittance is a neonate and an infant less than 2 months of age with UTI since in those patients there is a high risk of the development of a systemic infection [23, 26, 27].

If a bacterial urinary infection is suspected, empirical antibiotic treatment should be started as soon as possible. In most cases, before the start of the therapy, the exact causative agent and its sensitivity to antibiotics are not known. Treatment should start after sampling the urine for urine culture. The choice of antibiotic should be based on the knowledge of the local epidemiological situation, primarily regarding any resistance to antibiotics. In the treatment of isolated cystitis, oral antibiotics are prescribed to all patients that can tolerate oral intake [1, 3, 32]. Parenteral antibiotics are prescribed to patients with vomiting and dehydration. Most of the treatment guides for the treatment of UTI in children recommend cephalosporins of the first and second generation, amoxicillin-clavulanic acid, and nitrofurantoin [3, 11, 22, 23]. Due to the high incidence of resistance, certain guidelines do not recommend the use of trimethoprim-sulfamethoxazole as an empiric therapy except in cases when the sensitivity to this antibiotic is confirmed with an antibiogram. If urine culture shows that an empirically chosen antibiotic is not appropriate for that infection, in case of a clinical improvement the chosen antibiotic should be continued [26, 33].

The use of ciprofloxacin in the pediatric population is controversial and justified only when there is a severe clinical form of the infection, and there is no other antibiotic to which a particular bacterial strain is sensitive. It should be taken into account the fact that due to the frequent use of those antibiotics in the adult population, there is increased resistance to this group of antibiotics [34, 35].

Short-term antibiotic treatments are becoming more popular, due to better compliance, decreased expenses, and decreased incidence of antibiotic side effects. Most of the guidelines for cystitis treatment recommend the use of antibiotics over 3–5 days. If the response is not satisfactory after 2–3 days after the start of the therapy, a change of the antibiotic should be considered based on the antibiogram [1, 22, 23, 26, 36].

Symptomatic therapy should include hydration, and in cases of pronounced dysuria, analgetics should be considered [11, 37].

The use of antibiotic prophylaxis over the decades in children with recurrent and complicated urinary tract infections is believed to have contributed to the preservation of kidney function in many patients. Its true benefit is nowadays a matter of debate, as well as the contribution of such a prophylactic use of antibiotics to the development of increasing antibiotic resistance [36, 38]. Analyzing numerous studies dealing with this issue, a consensus has been reached for patients with high-grade VUR (III–V) and repeated UTIs (three and more over a year). Another group of patients at risk and deserving of prophylactic use of antibiotics are patients with dysfunctional voiding and secondary VUR [22, 39]. The antibiotic of choice should be nitrofurantoin, although there are studies on the prophylactic use of cefaclor and trimethoprim-sulfamethoxazole [22, 32]. One should keep in mind the growing resistance of proteus to nitrofurantoin [40]. The dosage should be 1/3 of the therapeutic dose of the chosen antibiotic. The duration of prophylactic use should be individually determined [23, 26].

In cases of fungal urinary tract infection, systemic antimycotic therapy is indicated. Asymptomatic fungal cystitis in otherwise healthy children does not need any treatment. In cases of fungal infection in neonates, infants, and immunocompromised children, as well as before invasive urological procedures antimycotic therapy is recommended for the prevention of systemic infection. Symptomatic cystitis treatment with fluconazole as an antimycotic of choice is recommended for two weeks, or in cases where fluconazole is not an option, same length of treatment with amphotericin B. There are some data on intravesical irrigation of the bladder with amphotericin B (500 mg/1 l of saline). However, there is a lack of sufficient randomized studies with clear treatment recommendations in this regard. Irrigation of the bladder in fungal cystitis should be considered in patients with refractory fungal cystitis with strains resistant to conventional antimycotic medications. In cases of urinary obstruction with “fungus ball,” surgical intervention is indicated [12, 41].

Viral cystitis in most cases resolves on its own. Complete regression of the symptoms happens after 2–3 weeks. Symptomatic therapy is usually sufficient. Lately, the use of cidofovir is discussed in infection with polyoma BK and Adenovirus. Due to its high level of nephrotoxicity, its use is still debatable, and further studies are necessary [2, 42].

Contemporary guidelines do not recommend treatment of asymptomatic bacteriuria, except before invasive surgical procedures (Tables 2 and 3) [11, 22, 43].

Medications	Dosage	Comment
Amoxicillin/clavulanic acid	20–50 mg/kg/day divided q8h	Based on amoxicillin component
Cephalexin	25–50 mg/kg/day divided q8h	/
Cefixime	8 mg/kg/day q24h	Age < 6 months safety and efficacy not established
Cefpodoxime	10 mg/kg/day divided q12h	Age < 1 months safety and efficacy not established
Cefuroxime	30 mg/kg/day divided q12h	Age < 3 months safety and efficacy not established
Nitrofurantoin	5–7 mg/kg divided q6h	Nitrofurantoin is not suitable for the treatment of cystitis + pyelonephritis, because of its limited tissue penetration.
Trimethoprim—sulfamethoxazole (TMP-SMZ)	8 mg/kg/day, divided q12h	Based on TMP component.; Contraindicated in hyperbilirubinemia and age < 1 months

Table 2.

Antibiotic agents for the oral treatment and prophylactic options of cystitis.

Prophylactic dosage should be 1/3 of the therapeutic dose of the chosen antibiotic.

If it is needed, adjust dose in renal insufficiency.

Medications	Dosage and route	Comment
Ceftriaxone	50–75 mg/kg/day IV/IM as a single dose or divided q12h	Do not use in infants age < 6 weeks may displace bilirubin from albumin
Cefotaxime	150 mg/kg/day IV/IM divided q6-8h	Safe to use in infants age < 6 weeks
Amoxicillin/clavulanic acid	100–150 mg/kg/day IV divided q6-8h	Indicated for complicated UTIs approved from birth and older
Amikacin	15 mg/kg/day IV/IM in single dose or divided q12h	/
Gentamicin	7.5 mg/kg/dose/day IV divided q8h	/

Table 3.

Antibiotic agents for parenteral treatment of cystitis.

For neonates and preterms consult neonatal antimicrobial guidelines.

If it is needed, adjust dose in renal insufficiency.

9. Imaging after UTI

Imaging after UTI is needed to rule out an underlying renal or urinary tract anomaly or the assessment of a renal injury.

Renal ultrasound is a useful diagnostic tool for evaluating urinary tract anomalies, urinary obstruction, renal structural anomalies, nephrolithiasis, calcification or an abdominal mass. In the last decade, the practice patterns have dramatically shifted, with far fewer patients undergoing voiding cystourethrogram (VCUG) after an initial UTI [1, 3]. Nevertheless, in children with abnormal ultrasound, atypical causative pathogen, complex clinical course or known renal scarring, and voiding cystourethrography should be considered to exclude vesicoureteral reflux [2].

DMSA scan is considered as the current gold standard for the assessment of renal parenchymal injury in children with a history of febrile UTI. However, most children with first febrile UTI do not need a DMSA renal scan [27]. It may be considered in children with recurrent febrile UTIs or renal parenchymal abnormalities on ultrasound [3]. Findings of renal scarring may influence surgical decision making in patients with surgically correctable conditions such as VUR. Renal scars on DMSA scans performed during or shortly after acute pyelonephritis may be due to preexisting acquired or congenital lesions or to the acute inflammatory reaction associated with APN. It is therefore recommended to perform a delayed DMSA scan at 4 to 6 months. A delayed scan allows the acute inflammatory reaction to subside, at which point any persistent cortical defects can be considered as renal scars, although in the absence of baseline scans, it may still be difficult to differentiate acquired from congenital lesions [3].

10. Prevention

Repeated cystitis is usually correlated with VUR, urolithiasis, or bowel and bladder elimination syndrome. All of those patients should be offered urotherapy, consisting of timed voiding (every 3 h), double micturition (to avoid residual urine), and other behavioral changes, including avoidance of urine withholding behavior in toilet-trained children. Specific management of obstipation should be offered for the patient. Biofeedback might be offered for patients with bowel and bladder elimination syndrome. In children with urolithiasis, the basis for the prevention of urinary infection is the management of the specific metabolic cause of urolithiasis, through dietary and medicamentous therapy. A very important factor in the prevention of urinary tract infections is adequate hydration [11, 44, 45, 46].

Antibiotics can harm gastrointestinal and periurethral flora, compromising in such a way the host’s defense mechanisms against pathogenic bacteria. The critical use of antibiotics in treating infections or other diseases is mandatory [3].

It has been scientifically proven that circumcision is beneficial in reducing the incidence of urinary infections in certain boys. Routine circumcision is, however, not recommended [19, 22].

The use of probiotics prevents colonization of the bowel with pathogenic bacteria with regular hygienic measures involving the prepuce and perineum. Their use is, however, not correlated with a significantly reduced incidence of recurrent UTIs [11, 47].

The prophylactic effects of cranberries have not been well documented. Some studies have shown that regular use of cranberry juice (minimum 6 months) reduces the number of repeated cystitis in children [48].

11. Complications

Usually, acute complication of cystitis includes dehydration, electrolyte disturbances, and febrile seizures. Intravenous hydration is necessary in more severe cases, often in younger children. Also, the use of some nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs and antibiotics, can lead to acute kidney injury [3, 49]. Severe blood loss as a consequence of hemorrhagic cystitis caused by chemotherapeutics is very rare but a significant factor affecting the morbidity and mortality in pediatric oncologic patients [2, 11].

If cystitis is not timely diagnosed and adequately treated, it can progress into pyelonephritis, carrying the risk of kidney scars and loss of kidney function in the future. Also, in the case of repeated cystitis with associated VUR or bladder dysfunction, there is a greater chance of renal scarring. In most children, renal scarring may not be clinically significant, but it may cause hypertension, proteinuria, and progressive decline in renal function as long-term complication of cystitis and UTI in general [49, 50].

Cystitis in the pediatric population in addition to being a health problem also has a great socioeconomic significance. Considering their frequency, tendency for recurrence, as well as the sequelae that can develop in the future, they have consequences not only for individual, but also for whole society.

12. Conclusion

Cystitis in children is usually a mild disease with a good prognosis. Nevertheless, due to specific conditions sometimes associated with cystitis in pediatric population (VUR, DSD…), it requires careful patient evaluation, adequate diagnostic procedures, and treatment. It is a common condition that is often undiagnosed and should not be underestimated.