ABSTRACT
Introduction: Among Gram-positive bacteria, enterococci are considered the most frequent pathogens in the case of urinary tract infections (UTIs) in children. It is known that enterococci have intrinsic resistance and acquired resistance is achieved by different mechanisms for: beta-lactams, aminoglycosides, quinolones, glycopeptides and linezolid.
Objectives: The purpose of this review is to demonstrate that Enterococcus spp. is a frequent cause of urinary infections in children and to analyze antibiotic resistance.
Materials and methods: The research was conducted using specific keywords such as "antibiotic resistance", "children", "UTI", "Enterococcus spp.", and "biofilm", in specialty books, Google Scholar, PubMed, ScienceDirect and PubMed Central (PMC).
Results: Antibiotic resistance of Enterococcus spp. is an issue in the choice of treatment for urinary tract infections. According to certain research, resistance to vancomycin has increased in some countries while decreasing in others. Another concerning problem is the observed gentamicin resistance, notably in Enterococcus faecium.
Discussion: Virulence factors, particularly Esp, which is involved in biofilm formation, play a key role in the processes of antibiotic resistance development. The presence of vanA and vanB genes modifies the structure of the bacteria and leads to the emergence of antibiotic resistance. Enterococcal resistance to vancomycin (VRE) represents a major public health problem and is the main mechanism that occurs in nosocomial infections.
Conclusions: Enterococcus spp. is one of the most prevalent etiological agents in urinary pathology and a common source of nosocomial infections. Because of the presence of virulence factors and genes, these bacteria can easily acquire resistance to specific antibiotics.
Keywords: antibiotic resistance, children, UTI, Enterococcus spp., biofilm
REZUMAT
Introducere: Dintre bacteriile Gram-pozitive, enterococii sunt considerați cei mai frecvenți agenți patogeni în cazul infecțiilor de tract urinar (ITU) la copii. Se știe că enterococii au rezistență intrinsecă și rezistență dobândită, care se realizează prin diferite mecanisme la: beta-lactamine, aminoglicozide, quinolone, glicopeptide și linezolid.
Obiective: Scopul acestei recenzii este de a demonstra că Enterococcus spp. este o cauză frecventă a infecțiilor urinare la copii și de a analiza rezistența la antibiotice.
Materiale și metode: Căutarea a fost efectuată folosind cuvinte cheie specifice, cum ar fi „rezistența la antibiotice", „copii", „ITU", „Enterococcus spp." și „biofilm", în cărți de specialitate, Google Scholar, PubMed, ScienceDirect și PubMed Central (PMC).
Rezultate: Rezistența la antibiotice a Enterococcus spp. este o problemă în alegerea tratamentului în infecțiile urinare. Potrivit anumitor studii de cercetare, rezistența la vancomicină a crescut în unele țări, în timp ce în altele a scăzut. O altă problemă îngrijorătoare este rezistența la gentamicină observată în special la Enterococcus faecium.
Discuții: Factorii de virulență, în special Esp, care este implicat în formarea biofilmului, joacă un rol cheie în procesele de dezvoltare a rezistenței la antibiotice. Prezența genelor vanA și vanB modifică structura bacteriilor și contribuie la apariția rezistenței la antibiotice. Rezistența enterococilor la vancomicină (VRE) reprezintă o problemă majoră de sănătate publică și este principalul mecanism care apare în infecțiile nosocomiale.
Concluzii: Enterococcus spp. este printre cei mai frecvenți agenți etiologici în patologia urinară și o sursă frecventă de infecții nosocomiale. Prin prezența genelor și factorilor de virulență, aceste bacterii pot căpăta cu ușurință rezistență la anumite antibiotice.
Cuvinte-cheie: rezistență la antibiotice, copii, ITU, Enterococcus spp., biofilm
1. INTRODUCTION
It is known that UTIs are very common in children of all ages. UTIs occur more often in the pediatric population under 1 year old, and more frequently in females. Primary UTIs can be defined as the first episode of diagnosed infection, most frequently in children under 1 year old, because of a high incidence of congenital anomalies of the kidney and urinary tract (CAKUT) and recurrent UTIs (RUTI), which result in incorrect treatment, antibioticresistant bacteria and end-stage kidney disease [1-4].
"Definition of UTI: urine culture containing ≥ CFU/mL in a midstream urine specimen, ≥ CFU/mL in a catheter urine specimen, or ≥ CFU/mL in a percutaneous nephrostomy (PCN) or suprapubic urine specimen, based on the EAU/ESPU guidelines" [5].
"Recurrent UTI definition: ≥ 2 UTIs within 6 months for having ≥ 3 UTIs within 1 year following the index of urinalysis (UA)" [5].
Pediatric UTI prevalence depends on age, gender and certain predisposing factors including neurogenic bladders [6], circumcision status, constipation, stool uropathogenic colonization, functional urinary tract diseases, anatomical abnormalities of the urinary tract (such as anterior-urethral valves, pelviureteric junction obstructions) causing obstruction to urinary flow (stasis), systemic diseases (diabetes, immunodeficiencies) and spinal pathology are among the medical conditions that may increase the risk for the development of UTIs. The probability of developing pyelonephritis during episodes of urinary tract infection (UTI) is closely correlated with vesicoureteral reflux (VUR), which is regarded as the most prevalent urologic abnormality in children. The incidence of VUR naturally declines as patients get older [7].
The most common symptoms in the case of UTIs are represented by: dysuria, pyuria, hematuria, pain in the flank along with changes in the macroscopic characteristics of urine (cloudy urine). These symptoms are absent among the children, so in order to detect a UTI, bacteriuria should be evaluated. UTI is considered when there is only one bacterial strain in the urine with a concentration of > CFU/mL [8].
The most common pathogens that are isolated are Escherichia coli, Klebsiella spp. and Enterococcus spp. [9-10]. Enterococci are Gram-positive bacteria that grow in pairs or short chains, catalase-negative and facultative anaerobes. The majority are γ-hemolytic on sheep blood agar, but some isolates can also have α- or β-hemolysis [2]. These bacteria are usually commensal in the intestine, but they are now known as emerging drug-resistant pathogens [7]. Enterococci are acquainted for their ability to grow in bile and to hydrolyze esculin. The most important species of enterococci are Enterococcus faecalis and Enterococcus faecium [2]. It is well known that these pathogens cause nosocomial infections nowadays. The most frequently isolated in urinary infections, intra-abdominal abscesses and bloodstream infections is E. faecalis [7]. In rare circumstances, when a child has UTI in association with a foreign body or after invasive techniques of diagnosis/treatment, E. faecalis must be considered as the etiological agent and empirical treatment must be administered [11]. The mortality rate is increasing in enterococcal infections due to a boost of drug resistance to ð›½-lactam antibiotics, aminoglycosides, glycopeptides and a weak response to therapy [12].
Urine culture is the gold standard for diagnosis, but it has several challenges, especially in young children, and it takes time to obtain results [13]. Urinary nitrite can be used as a test to rule out enterococcal bacteriuria, since Enterococcus spp. cannot convert urinary nitrate to nitrite [7].
It is advised to begin an empirical antibiotic medication as soon as feasible based on the child's age, the clinical presentation and the local epidemiology. In cases of clinical suspicion, fast urinary testing (urine dipstick) and urine microscopy can be used. To help choose an empirical antibiotic therapy, it is crucial to identify local trends of antibiotic resistance [13-14].
2. OBJECTIVES
The aim of this study was to investigate the microbiological diagnostic, virulence factors and mechanisms of antimicrobial resistance of Enterococcus spp. isolated from children with UTIs. In this article, Enterococcus spp. is discussed, because the majority of studies on UTIs in children reveal an increased prevalence of Gram-negative bacteria. These are Grampositive bacteria that are ignored due to their presence in enteric commensal flora and their contaminant role in urine culture.
3. MATERIALS AND METHODS
For this non-systematic review, 41 articles written in English that have been published in the last 5 years (2017-2022) were addressed. Also, two books on pediatric specialty were consulted for this article.
For this information to be found, the following databases have been accessed: Google Scholar, PubMed, ScienceDirect and PubMed Central (PMC).
To extract the research papers, relevant keywords have been used: "children", "Enterococcus spp.", "antibiotic resistance" and "biofilm formation".
The selected studies used European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Clinical and Laboratory Standards Institute (CLSI) standards for the interpretation of antibiograms. In order to identify the bacterial strains, the authors of these articles used MALDI-TOF MS (MatrixAssisted Laser Desorption Ionization - Time of Flight Mass Spectrometry) and 2 COMPACT.
For the management of bibliographic data, Zotero version 6.0.19 was used.
Inclusion criteria: children with recent or recurrent urinary infection with Enterococcus spp., vancomycin therapy, gentamicin therapy, other antibiotics used as alternatives, resistance mechanisms, sensitivity/resistance to other antibiotics, articles published between 20172022.
Exclusion criteria: adult population, urinary tract infections with a different etiology than the one studied, articles older than 2017, other pathologies produced by Enterococcus spp.
4. RESULTS
Most prevalent bacterial disease in children is urinary tract infection (UTI). It is expected that 7-8% of females and 2% of males will have a minimum of one UTI before the age of eight. Febrile UTI primarily affects newborns (both genders), whereas cystitis primarily affects females after the age of three [15]. Male patients under 1 year of age are more likely to develop urinary tract infections than female patients. After the age of one year, this ratio reverses [16].
Genitourinary malformations are a predisposing factor for UTIs. Some pediatric patients may also be at risk for UTI due to age, sex, malnutrition, or hospitalization. Bacterial infection was associated with sexual activity, previous episodes of UTI and invasive medical procedures of the urinary tract. As a result of differences in the anatomy of men and women, females are more likely to suffer from UTIs. Due to the female urethra being close to the anal region, the urethra becomes colonized by the anal bacteria. Because of this particularity, organisms from fecal flora may enter the bladder and kidney [8].
Over time, the bacterial diversity in the urine cultures of hospitalized individuals remained largely stable [12]. Gram-negative bacteria are the most common pathogens that are met in UTIs. Due to the specific structure of Gram-negative bacteria, which has the role of facilitating attachment to uroepithelial cells, the bacteria cannot be eliminated and for this reason, they will invade the tissue, causing infections and pyelonephritis. However, Enterococcus spp. is also in the top 3 among the most common pathogens which can lead to UTIs [8, 17]. The proportion of E. coli increases with age, while the proportions of Klebsiella spp. and Enterococcus spp. vary according to Huang et al [18].
There are also differences in the microbial flora and antibiogram of pediatric UTI depending on where the child lives and within that location. The widespread indiscriminate use of antibiotics, their ease of availability, and the over-the-counter sale of antibiotics have resulted in an increase in antimicrobial resistance among uropathogens over the past few decades [6].
To prevent issues like kidney scarring, it is crucial to start adequate empirical therapy for pediatric patients. Determining local resistance trends on a regular basis is required due to the rising prevalence of resistant bacteria and their major impact on the recommendations for early empiric therapy for UTIs [19].
In recent years, Enterococcus spp. have been a particular concern due to their capacity to spread quickly in hospital settings among healthcare personnel and hospitalized patients, and the genus has been identified as one of the primary bacterial genera causing nosocomial infections [20-21]. Along with the higher incidence rate, another key issue linked with Enterococcus spp. infections are their developing resistance to antimicrobial treatments [22-23].
Antimicrobial resistance (AMR) is one of the most serious risks to global health systems [24]. According to a United Nations International Committee study, infections caused by multidrug-resistant microorganisms (MDRs) might cause 10 million deaths by 2050, more than deaths due to cancer now [25]. Furthermore, it has been projected that MDR infections might cost up to $20,000 per patient, resulting in a worldwide health economic disaster [26]. The antimicrobial drugs used to treat these infections are frequently costly and toxic, with limited efficacy over time, leading to an increase in mortality [19].
Vancomycin resistance was initially identified in clinical strains of Enterococcus faecium and Enterococcus faecalis linked to an epidemic in Europe in 1988 [27]. Increases in the rate of enterococcal infections in the United States occurred in the early 1970s as a result of the development and use of thirdgeneration cephalosporins, and again in the early 1990s as a result of the use of vancomycin and more broad-spectrum antibiotics, as well as the evolution of more hospital-associated Enterococcus faecium [27].
According to European surveillance statistics, E. faecium has a varying VRE (vancomycin-resistant Enterococcus) incidence among countries, with less than 20% in Finland and the Netherlands and more than 20% in Ireland, Greece and Portugal. Italy has a low VRE prevalence (4.2%) [28]. According to Gupta et al., all of the isolates were highly susceptible to linezolid, teicoplanin, and vancomycin. Furthermore, the linezolid sensitivity rate was consistent with investigations done in India and Bangladesh, which found no Enterococcus spp. isolates resistant to linezolid. In contrast, the reported incidence of VRE in a single Brazilian institution was 15.8%. VRE was found at a greater prevalence in Iran (23.7%) and in Egypt (75.0%) [19].
Because of the fast spread of VRE, new antibiotics such as linezolid, teicoplanin, and tigecycline have been developed. Fortunately, this investigation found that Enterococcus isolates were very sensitive to these antibiotics; however, the rate of resistance to teicoplanin was higher than others, with values comparable to vancomycin [19].
Another antibiotic used in the case of VRE is fosfomycin, as an alternative treatment. This is administered in the case of community-acquired lower urinary tract infections, in the pediatric population. A broad-spectrum bactericidal antibiotic, fosfomycin has efficacy against both Gram-positive and Gram-negative pathogens, including bacteria that are multidrug resistant. Fosfomycin has demonstrated effectiveness in experimental biofilm models and has good tissue penetration. Its unique mechanism of action results in a synergistic effect with many antimicrobials. It also has an increased safety profile in children, even when used for prolonged periods of time. Since fosfomycin has various benefits for treatment in children with UTI (it is easy to administer, reaches high concentrations in urine, has few side effects and has no effect on gut flora), its properties make this antibiotic a very appealing alternative, particularly for treating infections caused by multidrug-resistant bacteria. Fosfomycin is not advised for use in monotherapy in the event of febrile UTI due to the possibility of resistance development during therapy [15, 29].
Another observed resistance was to gentamicin, detected in 60% of E. faecalis and E. faecium. More recent studies have shown that E. faecalis has a lower rate of resistance to gentamicin than E. faecium [30]. For the treatment of enterococcal infections, aminoglycosides such as gentamicin have a synergistic effect when combined with penicillin or glycopeptides [31]. This synergistic effect is lost if the strains are resistant to aminoglycosides [32].
In fact, high-level gentamicin resistance is related to an increase in mortality, according to population-based research in Denmark that examined a sample of over 1000 individuals with an Enterococcus infection. The prevalence of high-level gentamicin resistance should be addressed in prosthetic surgery when gentamicin might be utilized in biomaterials to lower the risk of infection [19].
In several investigations on Enterococcus spp. in UTIs, resistance to erythromycin, penicillin G, ampicillin, gentamicin, levofloxacin and ciprofloxacin (Nanjing, China) was observed, in contrast to the Shiraz study, where nitrofurantoin, ampicillin and gentamicin were effective. This indicates that the resistance of Enterococcus to antibiotics depends on the geographical area and the therapy administered to the patients [12, 17, 33].
5. DISCUSSION
Globally, there has been an upsurge in multi- and pan-drug resistance, which is a hazard to public health. Recent studies have revealed an increase in bacterial infections that are multidrug-resistant and come from many sources, which has raised the necessity for adequate antibiotic usage and the identification of the most effective antibiotic [18]. Antibiotic resistance was also analyzed according to the antibiogram made from the pathological organisms isolated from pediatric patients with urinary tract infections. The resistance profile of bacteria varies according to a variety of circumstances, including the patient's features and geographical origin [15].
To provide suitable suggestions on empiric therapy for these pathogens, the local resistance rates should be evaluated [15]. For example, VRE is currently one of the top six AMR phenotypes responsible for healthcareassociated infections in the United States [27].
Infections produced by enterococci have prompted special worry in recent years due to their capacity to develop resistance to many antimicrobial medications used in clinical practice and to cause severe life-threatening infections in patients [19, 34].
The increased use of antibiotics, the coexistence of this bacterium with other bacteria in the intestine that carry genetically transmissible resistance mechanisms and their capacity to acquire these genetic mechanisms, have all contributed to the emergence of strains that confer resistance to different classes of antimicrobials [35].
The virulence determinants of Enterococcus spp. are found on transmissible genetic elements like plasmids and transposons and/or on the chromosome in pathogenicity islands and they play a role in colonization, tissue damage and escape from host immune responses. These components, including the enterococcal surface protein (Esp), aggregation substance (ASA), PavA-like fibronectinbinding protein (EfbA) and adhesion to collagen of E. faecalis (ACE), cytolysin (CYL) and gelatinase (GelE) play different roles in colonizing urinary tract tissue, evading the host immune system, and dispersing bacteria throughout the body. Although there is less information on this association, the presence or lack of these virulence genes may affect E. faecalis colonization and infection in the urinary tract tissue [35].
Esp, EfbA, ASA, ACE, CYL, GelE encoding genes and tetracycline resistance determinant (tetM) gene are the primary virulence genes, while ddl is a species-specific gene for E. faecalis [35]. CYL is a cytolysin and was one of the first virulence factors discovered in both E. faecalis and E. faecium [36]. Asa1 is a pheromone-inducible protein that promotes bacterial adhesion to renal tubular cells as a virulence factor. Furthermore, the endocarditis and biofilm-associated pili (ebp) gene, which includes ebpA, ebpB, and ebpC, is involved in the creation of pili by enterococci and is required for bacteria to cause UTI [37]. It is recognized that the chromosomal resistance determinant tetM mediates tetracycline resistance through ribosomal protection. The presence of other genes, such as tetO and tetS, in these isolates in hospital environments, can provide resistance to tetracycline as well as minocycline [35, 38]. The adhesin function of the Esp may help bacteria colonize the urinary system or remain there longer [35]. Esp is a cell wall-associated protein that has been suggested to have a key role in bacterial colonization, urinary tract persistence and biofilm formation [37].
Bacterial biofilms have a great impact on recurring UTIs and antimicrobial resistance. The formation is difficult to eliminate due to the antibiotic resistance phenotype. As a result, for the treatment of bacterial biofilm-associated infections, combination therapy is advised [37].
There are several enterococcal virulence factors associated with biofilm development that have been discovered. Important components involved in biofilm development include Asa, Esp and Ebp [39]. However, there have been conflicting findings on the significance of enterococci virulence genes, especially the Espencoding gene, in biofilm development. As per certain studies, several virulence factors and environmental circumstances, such as nutrient content in the medium, might influence the biofilm development of enterococcal isolates [37, 39].
Biofilm protects enterococci against the human immune system and antibiotics, typically responsible for recurrent, chronic and antibiotic-resistant infections. Additionally, a powerful biofilm producer in many bacterial species reveals multidrug resistance [11]. Most scientists claim that E. faecium isolates generate biofilms more frequently than E. faecalis isolates [37].
The accumulation of genes granting resistance to several antibiotic classes, such as beta-lactams, aminoglycosides, fluoroquinolones and glycopeptides, has been the most notable aspect of this genomic expansion within E. faecium. The clinical importance of VRE infections has led to a considerable portion of research efforts being devoted to determining the transmission of vancomycin resistance genes. The related D-Ala-D-Lac ligases encoded by the vancomycin/teicoplanin A-type resistance protein (vanA) and vancomycin B-type resistance protein (vanB) genes provide substantial levels of resistance to glycopeptide antibiotics. However, the regulation of the vanA and vanB loci varies. Only the vanA gene cluster reacts to teicoplanin exposure, whereas treatment with vancomycin causes both the vanA and vanB gene clusters to express. Plasmid transfer or transposon integration can enhance the transmission of both vanA and vanB [36].
VRE is currently a major nosocomial infection all over the world and produces a wide variety of illnesses, including urinary tract infections. The capacity of enterococci to build refractory biofilms, colonize and express virulence factors, being antibiotic resistant makes it an essential nosocomial pathogen. The rise of VRE has boosted the usage of other antibiotics such as daptomycin and linezolid, against which enterococci are becoming increasingly resistant. To combat this issue, epidemiological surveillance studies are required to enhance clinical antibiotic usage and prevent antibiotic overuse and misuse [19, 40].
Many studies have found that bacteremia produced by VRE strains is more likely to result in death than bacteremia caused by vancomycin-sensitive pathogens. AMR is a problem all over the world because it increases morbidity and mortality also, the antibiotics used to treat infections with multidrugresistant organisms are frequently costly, with limited efficacy over time, leading to an increase in mortality by toxicity [19, 41].
Finally, all of these changes that appear at the genetic level are most typically caused by the overuse of antibiotics, which can activate dormant genes [35].
6. CONCLUSIONS
The etiology of urinary infections can be varied, although E. coli is the main pathogen highlighted in most studies, Enterococcus spp. is also in the top three, being the main Grampositives agent. It was the first bacteria t caused nosocomial infections and can spread very quickly among medical departments in hospital units and healthcare staff. Is essential for the proper management of urinary infections in children because they are linked to long-term complications.
Knowing the genes that play an important role in the development of antibiotic resistance, is critical in order to act quickly by providing therapeutic options and preventing the emergence of new gene mutations. Resistance to antibiotics, especially to vancomycin, has increased in different geographical regions so new classes of antibiotics (e.g. linezolid and daptomycin, against which enterococci are becoming increasingly resistant) have been introduced in the treatment of urinary tract infections.
The interaction of vancomycin with the vanA and vanB leads to the activation of these genes resulting in resistance to this antibiotic. A peculiarity of the expression of the vanA gene is that it also produces resistance to teicoplanin. VRE has a higher mortality rate than in the case of strains susceptible to vancomycin. The antibiotic therapy used in such infections is expensive with reduced effectiveness and which has repercussions on the patient's state of health, implicitly in increased mortality due to the occurrence of toxicity. The emergence and formation of biofilm, as well as the evolution of antibiotic resistance, are all influenced by virulence factors.
Consequently, any aspect regarding the geographical region, the type and the dose of antibiotic used leads to genetic changes in enterococci, which have the effect of increasing resistance to antibiotics and finally to the inability to treat infections (including UTIs). This represents a burden for the public health system, in terms of costs, but especially for patients whose lives are at risk.
Conflict of interest: The authors have no conflict of interest to disclose.
Disclaimer: The views expressed in the submitted article belong to the authors and are not an official position of the institution.
Funding: This work received no funding.
Ethical approval: Not applicable.
Informed consent: Not applicable.
*Corresponding author: Crina Dănăilă; e-mail: [email protected]; https://orcid.org/0000-0003-0250-3325
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Abstract
Introduction: Among Gram-positive bacteria, enterococci are considered the most frequent pathogens in the case of urinary tract infections (UTIs) in children. It is known that enterococci have intrinsic resistance and acquired resistance is achieved by different mechanisms for: beta-lactams, aminoglycosides, quinolones, glycopeptides and linezolid. Objectives: The purpose of this review is to demonstrate that Enterococcus spp. is a frequent cause of urinary infections in children and to analyze antibiotic resistance. Materials and methods: The research was conducted using specific keywords such as "antibiotic resistance", "children", "UTI", "Enterococcus spp.", and "biofilm", in specialty books, Google Scholar, PubMed, ScienceDirect and PubMed Central (PMC). Results: Antibiotic resistance of Enterococcus spp. is an issue in the choice of treatment for urinary tract infections. According to certain research, resistance to vancomycin has increased in some countries while decreasing in others. Another concerning problem is the observed gentamicin resistance, notably in Enterococcus faecium. Discussion: Virulence factors, particularly Esp, which is involved in biofilm formation, play a key role in the processes of antibiotic resistance development. The presence of vanA and vanB genes modifies the structure of the bacteria and leads to the emergence of antibiotic resistance. Enterococcal resistance to vancomycin (VRE) represents a major public health problem and is the main mechanism that occurs in nosocomial infections. Conclusions: Enterococcus spp. is one of the most prevalent etiological agents in urinary pathology and a common source of nosocomial infections. Because of the presence of virulence factors and genes, these bacteria can easily acquire resistance to specific antibiotics.