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Lietuvos Sveikatos Mokslu Universitetas
LSMU
Severe Staphylococcus aureus infections in children, clinical
presentation and outcome
Kevyn Maldonado Vela
Medicine, 6th year
Group 35
Supervisor: PhD Vaidotas Gurskis, head of Pediatric Intensive Care Unit
Faculty: Pediatrics
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Table of Contents
TABLE OF CONTENTS ... 2
SUMMARY ... 3
ETHICS COMMITTEE CLEARANCE ... 5
ABBREVIATIONS LIST ... 6
INTRODUCTION 5.1 History ... 6
5.2 Overview ... 6
AIM AND OBJECTIVES ... 9
REVIEW OF THE LITERATURE ... 9
METHODS AND PROCEDURES 9.1 Literature search and search strategy ... 20
9.2 Data collection ... 20 9.3 Results of search ... 20 9.4 Exclusion criteria ... 21 9.3 Study selection ... 22 RESULTS ... 23 CONCLUSIONS ... 24 REFERENCES ... 25
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ABSTRACT
Kevyn Maldonado Vela
BACKGROUND: Staphylococcus aureus is one of the most important species of staphylococci. Bacteria in the gennus Staphylococcus are pathogens of man and other mammals. And they are divided depending on their ability to clot blood plasma thansk to the coagulase reaction. Staphylococcus aureus has coagulase positive and its a marker for Staphylococcus aureus. It can be found either in the environment (in community environment and clinical environment) and frequently seen as normal flora bacteria in people , and thats why, Staphylococcus aureus is a major opportunistic pathogen that can cause many forms of infection. The way children get infected with Staphylococcus aureus is mainly when the skin is punctured or broken, where the bacteria can enter the wound an cause infections.
METHODS: A literature search was conducted using PUBMED, ScienceDirect and MEDLINE databases using key word searches „severe“, „Staphylococcus“ aureus and „children“. No restrictions were placed on study date and design of publication. The abstracts were examined and full text of articles for all remaining articles were retrieved.
MAIN RESULTS: Systematic literal review was done and it was compiled the latest and most updated information about Staphylococcus aureus in children. It was inevestigated the clinical outcomes of the bacteria on the respiratory system and skin and soft tissue infection and its severity. Additionally, risk factors were estalished according to the several abstract analyzed. As well as its treatment and resitance pattern against antibiotics.
CONCLUSIONS: The prevalence and increased risk of carriage and infection among patients depends on the usage of antibiotics in the last 3 months, as well as the lower social situation and economical. Additionally, the presence of PVL on Staphylococcus aureus indicates an increased severity in the clinical outcome.
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Acknowledgments
I would like to thank Dr. Vaidotas Gurskis for his support and help throughout this process.
Conflicts of interests
The author reports no conflicts of interest
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Methicillin-resistant Staphylococcus aureus - MRSA Methicillin-susceptible Staphylococcus aureus - MSSA Multiple drug resistant Staphylococcus aureus – MDRSA Bronchoalveolar lavage - BAL
Area under the curve/minimum inhibitory concentration ratio- AUC/MIC Spa typing, multilocus sequence typing - MLST
Staphylococcal cassette chromosome mec - SCCmec) Pulsed-field gel electrophoresis - PFGE
Concentration trough - Ctrough Lactobacillus plantarum extract - LPE Panton-Valentine leucocidin - PVL
Community acquired methicillin-resistant Staphylococcus aureus - CA-MRSA Fibronectin binding protein A - fnbA
Small-colony variants - SCV
Human immunodeficiency virus - HIV
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History: Staphylococcus aureus was discovered by Scottish surgeon Alexander Ogston (April 1844- February 1929) in 1880. He was the first study wound infection in humans, he examined pus from every abscess he could find and then he tried several ways to grow the bacteria. He found the best medium was the hen’s egg. He noticed and wondered why some micrococci were harmless, but when in 1882 he was chosen to be Regius Professor of Surgery in Aberdeen, he left his investigation due to lack of time and left to others to continue with his work. What his work left was the discovery and description of the staphylococcus and hypothesized the major cause of pus.
It was Friedrich Julius Rosenbach (December 1842 – December 1923), a German physician and microbiologist, who was accredited the name of “staphylococcus” by the official system of
nomenclature at the time, as he could grow the bacteria on solid media and differentiate the colonies. He noted the two types of colony that differ from each other by color and he called them
“Staphylococcus pyogenes aureus” and “Staphylococcus pyogenes albus” (this later species is now named Staphylococcus epidermis).
Overview: Staphylococcus (From the Greek staphyle (bunch of grapes) and kokkos (berry)) aureus (from the Latin aurum, gold) is a microbial agent that frequently is cause of infection, in the community as in the clinical environment. Oftenly Staphylococcus aureus colonizes nasal passage and axillae of people and they are a common human skin commensal. The infections that can bring a great risk, even life threating condition. Stapylococcus aureus infections could be: skin lessions and abscesses, deep-seated infections, such as osteomyelitis and endocarditis, and infection in surgical wounds. It can cause food poisoning by releasing enterotoxins into the food. The biological mechanisms which Staphylococcus aureus leads to disease is by many potentital virulance factors: surface proteins that lead colonization of host tissues, factors that probably inhibit phagocytosis, toxins that damage host tissues and cause disease symptoms...
Toxins that Staphylococcus aureus can express are several different types of protein toxins. The best characterized and most potent membrane-damaging toxin is α-toxin. Other toxins that can express
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Staphylococcus aureus are β-toxin, δ-toxin, γ-toxin and leukocidin. Enterotoxins when ingested can cause food poisining and leading to cause diarrhea and vomitng.
One of the β-toxin is known as Panton-Valentine leukocidin. It‘s presence is associated wit an increase in the virulance of certain strains of Staphylococcus aureus, specifically, in the majority of community-associated Staphylococcus aureus, and it is the cause of necrotic lesions such as hemorrhagic pneumonia due to the action of leukocyte destruction. This lesions involve the skin and the mucosa.
The genus Staphylococcus consist of gram positive cocci aerobic organisms, with a size about 0.5 to 1.5 μm. They are grouped as single cells, in pairs, tetrad, short chains or forming clusters of grapes. They are non-mobile bacteria, not sporulated, they do not have a capsule, although some strains develop a slime capsule. Most of them produce catalase (enzyme that can split the hydrogen peroxide in water and free oxygen). Also, Staphylococcus aureus produce protein enzymes called coagulase, which is important to identify and distinguish from other types of Staphylococcus isolates. For Staphylococcus Aureus, they are grouped in clusters (resembling grapes), they are nonmotile and non-spore-forming spherical bacteria and they are facultatively anaerobic.
Many molecular typing methods have been applied to the epidemiological analysis of Staphylococcus aureus such as plasmid analysis, but this method has the disadvantage that plasmids can be easily lost and acquired and are therefore unreliable. Other methods as ribotyping and random primer PCR. But the method currently known as the most reliable is pulsed field gel electrophoresis, where the genomic DNA is cut with a restriction enzyme that generates large fragments.
Since the beginning of the antibiotic era, Staphylococcus aureus has responded to the introduction of new drugs by rapidly acquiring resistance by a variety of genetic mechanisms. In the recent years, there is an increase in antibiotic-resistant strains of Staphylococcus, specifically MRSA (Methicillin-resistant Staphylococcus Aureus). Those are specially dangerous for children. MRSA can cause outbreaks in hospitals and can be epidemic. The children may carry the Staphilococcus aureus but not get infected or sick. A carrier of MRSA can give it to other people and make them sick.. This means that it spreads easily from person to person. Children can catch MRSA inside or outside of a hospital. MRSA may
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cause a mild, severe, or deadly infection in children's body. The infection may be in your child's skin, blood, lungs, heart, or brain. The most important Staphylococcus infections for children are cellulitis, impetigo and staphylococcal scalded skin syndrome.
No vaccine is currently available to combat staphylococcal infections. There may now be a case for considering methods to prevent disease, particularly in hospitalized patients. This methods consist of hyperimmune serum from human volunteer donors.
Children tend to get more infections than adults, not by the fact that their immune system is less matured than adults. By the time children are in school-age, their rate of infection is usually the same as the rate for adults. Therefore, the reason they get more infections is by the cause of infection. Children that are in day care centers, schools... they play with each other and can give infection to each other. Younger children drool and their noses drip, touch and share toys. As an adults, we dont have that much of contact with each other, so we are less likely to catch so many infections. Therefore, we need appropiate diagnostic criteria, specially in the cases where there is resistant to antibiotics in children infected by Staphylococcus aureus and study its peculiarities on children.
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Aim and Objectives
Aim: This research aims to collect the peculiarities, clinical features and outcomes found on children affected by Staphylococcus aureus.
Objectives: The research will try to gather the newest and most updated information and knowledge about Staphylococcus aureus in children and to evaluate clinical characteristics. To know the risk factors and patterns of resistance of the bacteria. To understand the relation of Staphylococcus aureus and Panton-Valentine leucocidin (PVL). It will help to understand how the bacteria affects children and how it differs from adults, therefore improving the diagnostic criteria in children affected by Staphylococcus aureus.
Literature review
Study characteristics
The 20 studies that were included in the review and analyzed will be mention below here.
(1) This study was made to identify the risk factors that are associated with the presence of methicillin-resistant Staphylococcus aureus (MRSA) aureus in surgical cultures taken from abscesses that are formed in the neck and head in the pediatric patients. The participants were pediatric patients under the age of 18 years and with head and neck abscesses. Methicillin-resistant Staphylococcus aureus nasal swab cultures were taken and then they were compared to surgical cultures and correlation was made. Of total of 272 patients, there were 68 (25%) MRSA-positive abscesses. The majority (86.8%) of these abscesses were in children under 2 years of age. Overall, 12 (4.4%) presented with positive admission MRSA nasal swabs. Of these, 91.7% had MRSA-positive abscess cultures. Decreasing age in years showed an odd ratio of 1.650 (P < 0.001) for MRSA-positive abscess, with children less than 1 year old having the highest odd ratio of 10.74 (P < 0.001). This study showed the correlation that the younger age of the patient, there is major risk of MRSA nasal colonization and more risk to develop MRSA abscess of the head and neck. Therefore, children under 2 years of age or those with MRSA nasal
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colonization can be considered a high-risk population that may benefit from empiric antibiotics against MRSA.
(2) Antimicrobial resistance patterns can significantly differ in adult and children, and the location of the population. In India is estimated that has the highest neonatal mortality due to neonatal sepsis caused by bacteria resistant to first-line antibiotics. During the research is analyzed several pathogens from blood cultures from patients. Among Gram-positive bacteria, Staphylococcus aureus was found to be the most common isolate (median, 14.7%; interquartile ranges (IQRs), 7.4% - 25.6%). From the Staphylococcus aureus isolates, 50% were methicillin-resistant Staphylococcus aureus. Another resistance found and noted were to erythromycin (53%), cefotaxime (57%) and cotrimoxazole (57.7%). No resistance was found to vancomycin, linezolid, and teicoplanin in all the Gram-positive bacteria that were investigated.
Therefore, pediatricians should be encouraged in participate and adapt in active surveillance for antibiotic resistance. And it is urgently needed the awareness of antibiotic resistance and rational antibiotic use among pediatricians.
(3) The community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) has several strains, one of those strains is known as MRSA USA300. This research is based on this specific strain about its carriage, infections and risk factors in skin and soft tissue infection on children. The study was done on the pediatric emergency department, nasal and axillary swabs were made to collect. The cultures were categorized between carriers of MRSA USA300 and carriers of non-MRSA USA300. After analyzing them, it was found that MRSA USA300 carriage rate was higher in children less than two years of age, those with a skin and soft tissue infection, children with recent antibiotic use and those with family history of skin and soft tissue infection. Also, the carriers for MRSA USA300 were more probably to have a lower income compared to non-MRSA USA300. Additionally, rates of Panton-Valentine leucocidin (PVL) genes were higher in MRSA carriage isolates with a skin and soft tissue infection, compared to MRSA carriage isolates of patients without a skin and soft tissue infection. Therefore, there
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was an association between MRSA USA300 carriage and presence of PVL in those diagnosed with abscess.
(4)The area under the inhibitory concentration curve (AUIC) defines drug regimens as a ratio of drug exposure to minimum inhibitory concentration (MIC) and allows them to be compared with each other. Thus, a low AUIC values, directly correlate with drug resistance.
Adult guidelines suggest an AUC/MIC of >400 to a vancomycin trough of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but getting these troughs in children is difficult. The research aims to assess the likelihood that 15 mg/kg of the drug every 6 hours in a child achieves an AUC/MIC >400.
Participants’ age was between 2 months and 18 years with a positive Staphylococcus aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Two groups were made, first one getting 15 mg/kg of the drug every 6 hours and the second getting any other dose and intervals.
In the group 1, probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L. In group 2, probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. Therefore, the study demonstrated that is possible that children get the AUC/MIC > 400 with the specific dose analyzed.
(5) It was investigated the antimicrobial susceptibility and molecular characteristics of Methicillin-resistant Staphylococcus aureus isolated from children treated at Shenzhen Children's Hospital. During investigation, 140 MRSA strains were
characterized by antimicrobial susceptibility testing and it was found that all 140 MRSA isolates were resistant to oxacillin and penicillin, but susceptible to nitrofurantoin, quinupristin, vancomycin, levofloxacin and moxifloxacin. Additionally, resistant to erythromycin (77.8%), clindamycin (75.0%), and tetracycline (55.6%), and 7.4% and 3.7% were resistant to sulfamethoxazole/trimethoprim and gentamicin, respectively. Only 3.7% and 7.4% of isolates exhibited intermediate susceptibility to ciprofloxacin and rifampicin,
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respectively. Then further performed spa typing, multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec), pvl gene and pulsed-field gel electrophoresis (PFGE). ST59 was the most common from MLST lineage (54.3%) and most MRSA isolates belong to SCCmec IV (64.3%) and V (22.8%). It was mentioned before the strain Methicillin-resistant USA300 (MRSAUSA300), it’s a strain reported in USA, Europe, Asia-Pacific region… in China, the most widespread strain in skin and soft tissue infections is currently ST59-SCCmec IV. The MRSA-ST59-SCCmec IV-t437 clone was the most predominant strain detected.
(6) Vancomycin is an important drug on the treatment of methicillin-resistant Staphylococcus aureus (MRSA). And it is of importance to know the effects and outcomes of the range of doses for this drug on children with MRSA bacteremia. The doses used was determined by the reference of “Pediatric and Neonatal Dosage Handbook”. During the investigation, 2 groups were made to differentiate the outcomes, the group 1 with children with initial vancomycin concentration (Ctrough) < 10 μg/mL and group 2, ≥ 10 μg/Ml. The clinical and microbiological outcomes were compared between groups to reach a conclusion. The possible outcomes were: recurrence of infection, resolution of fever and all-cause fatality within 30 days; and microbiological outcome: persistent bacteremia after 48-72 hours. The result of the study after analyzing 45 cases for clinical outcomes and 36 cases for microbiological outcomes and it showed no statistically significant difference between the two groups with initial vancomycin Ctrough < 10 μg/mL and ≥ 10 μg/mL, in terms of clinical outcome including 30-day mortality and recurrence (P = 0.899, and P = 0.754, respectively). Although, in the group 1 was observed more frequently persistent bacteremia at 48 hours. Additionally, during investigation was not possible to identify statistically significant predictors for persistent bacteremia at 48–72 hours and 30-day fatality. (7) The antimicrobial and the anti-biofilm activity of Lactobacillus plantarum extract (LPE) for oral Staphylococcus aureus and Staphylococcus aureus ATCC 259523 was assessed by microtiter plate and atomic force microscopic assays, and the study showed that LPE might have some activity of resistance-modifying by showing an anti-biofilm activity that is an importance factor of oral bacteria, but also the study specified that it is unknown the active compound responsible for this.
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(8) It has been often associated the toxin Panton-Valentine leucocidin (PVL) with more infective properties of Staphylococcus aureus, but at the moment has been unclear. The investigation researched for the presence of PVL genes in methicillin-resistant Staphylococcus aureus (MRSA) and methicillin sensitive (MSSA) in children and a correlation is made. Presence of PVL in staphylococcus aureus accounts for 73.91%, out of them, 80.92% of MRSA and 67.59% of MSSA. It was found a relation between resistance to erythromycin and lack of PVL and that presence of PVL was higher in older patients. Additionally, presence of PVL on MRSA and MSSA determine that there is no direct relation between infection and presence of PVL genes but that further investigation is required.
(9) The research shows the percentage of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) during the investigation of 345 children identifying colonization with standard microbiological test and sensitivity to certain antibiotics. 20 children (5.8%) were colonized with CA-MRSA, 86 children (24.9%) with Methicillin Susceptible Staphylococcus aureus and 239 cases (69.3%) didn't have Staphylococcus aureus colonization. It didn’t differ the results through the different ages of the participants or gender. Investigation also showed the lowest resistance for CA-MRSA is gentamicin, rifampin and trimethoprim-sulfamethoxazole.
(10) The research analyzed if Staphylococcus enterotoxins could infect the middle ear as it can infect the upper airway, thus causing otitis media with effusion. Aspiration from the middle ear was made and analyzed from 24 children for bacterial culture and 24 controls. And results shown that only one enterotoxin was discovered in 6 out of 25 children and in 3 of 24 controls. Therefore, according to this, there is some presence of the enterotoxins but no evidence that they could have started in the infectious process in patients with otitis media.
(11) Staphylococcus aureus can be cause of community-associated pneumonia in children. Study shows that during molecular investigation, it was identified the following strains by PCR: mecA, Panton-Valentine leucocidin (PVL) and fibronectin binding protein A (fnbA). From the 41 cases studied, 31 cases (75.6%) were of methicillin-resistant Staphylococcus aureus. Complication occurred, showing empyema (61%), pneumatoceles (17%) and lung abscess (2.5%). Intensive care unit was required for
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58.5%, and two deaths happened (4.9%). During treatment, bacteria didn’t show resistance to vancomycin, teicoplanin and linezolid, and showing just resistance to clindamycin in 26.8%.
PVL gene positive was found in 90% of the methicillin-resistant strains and from methicillin-sensitive strains shown 3/5 PVL positive.
(12) The investigation that was conducted in 7 different European countries tried to show the relation of the Methicillin-resistant Staphylococcus aureus (MRSA) and Panton-Valentine leucocidin (PVL) in severity of the infection disease that they cause. The study searched through 152 patients and concluded that PVL is associated with more severe infections and that it doesn’t depend of the presence of methicillin resistance.
(13) The study finds a relation between community acquired Staphylococcus bacteremia and the presence of strains of Methicillin-resistant Staphylococcus aureus (MRSA)and Methicillin-sensitive Staphylococcus aureus (MSSA). And among of the 208 children investigated, 136 children (65%) were identified with MRSA. Additionally, in cases with MRSA were found higher rates of persistent bacteremia, admission to the Intensive Care Unit and surgery. It is suggested that as treatment vancomycin and clindamycin should be used as clindamycin only showed resistance to 9% of the cases. (14) Staphylococcus aureus infection might appear after a respiratory viral infection, and the study investigates if toxin known as alpha toxin might have relation with the infection itself. The study, after analyzing children in intensive care units showed that alpha toxin was found the most in Methicillin-resistant Staphylococcus aureus coinfection with respiratory viral infection which suggest a relevant role of the alpha toxin. This supports the therapy of neutralizing the toxin, which will decrease the severity of the pathology if given properly.
(15) In the region of Kashan, Iran, it was studied the multidrug resistance of the Staphylococcus aureus to see its prevalence on nasal carriage. From the subjects analyzed (350 children), 92 Staphylococcus aureus isolates were found of which 33 (35.9%) were Methicillin-resistant Staphylococcus aureus and 27 (29.3%) were multidrug resistant. The resistance shown by the multidrug resistant were to cephalothin, co-trimoxazole, clindamycin, ciprofloxacin, vancomycin and to oxacillin. It was also found
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that subjects who had been under usage of antibiotics on the last 3 months, family size of more than four members and passive smoking at home, were at higher risk for nasal carriage of multidrug resistant Staphylococcus aureus.
(16) A decolonization of bacteria might be linked to decrease the probabilities of infection. This study shows by two different approaches of eradication of Staphylococcus aureus: by decolonizing the entire household environment and decolonizing the individual. The study demonstrates that decolonization of the household by hand washing, rinse of face, used of soaps and lotions… wasn’t more effective than decolonization in cases of Staphylococcus carriage, but it helps for prevention.
(17) A variant of Staphylococcus aureus is known as Small-colony variants (SCV) and the study investigates if there is a prevalence of this kind of variant in children with cystic fibrosis. Samples were taken from 41 children from lower respiratory tract but during the analysis it wasn’t found any SCV. So was concluded that this kind of variant may not give complications in children with cystic fibrosis. (18) The immune response of the body against colonization of Staphylococcus aureus in the lungs of children with cystic fibrosis is shown in this study. Specifically, the immune action against the exotoxins LukAB, alpha-hemolysin and Pantene-Valentine leucocidin. It was analyzed 50 children with cystic fibrosis by antibody assessments and specifically assess its function against LukAB by geometric mean titers. Study concluded and showed that the toxin lukAB was expressed by Staphylococcus aureus and immune action against was detected during infection in cystic fibrosis and exacerbation state.
(19) During this study, it was investigated the prevalence of the presence of Methicillin-resistant Staphylococcus aureus in Human immunodeficiency virus (HIV) pediatric patients, for nasal, skin and perineal carriage. Among the 400 participants, 206 of them were identified with Staphylococcus aureus. Of this colonization found, study showed only 16.8% was of Methicillin-resistant Staphylococcus aureus and was associated with male gender, use of antibiotics last 3 months and high account of CD4 T-cell. Study concluded there is a high rate of colonization among HIV patients.
(20) The study investigated the diagnostic value of bronchoalveolar lavage (BAL) in children with nonresponding community acquired pneumonia. And during the research, it was found that
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Staphylococcus aureus was on the most frequently bacteria isolated together with Streptococcus viridians and Pseudomona aeruginosa. This concluded the important diagnostic value of BAL to identify cause of pneumonia, therefore guiding the proper treatment for children.
The table below provides a brief information about the included studies as like their characteristics and results (Table 1).
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Table 1 – Study characteristics Study
Reference
Population Profile Cases/Controls /Participants Conclusion [1] Bradford et al Patients from hospital 272 patients 68 cases
Younger age is a risk factor for MRSA colonization that develops into head and neck abscesses.
[2]
Dharmapala n et al
Indian neonatal and pediatric patients
1179 studies 82 cases
Found high rates of resistance to several antibiotics. Recommendation of guidelines of treatment [3] Immergluck et al Pediatric patients from Atlanta, Georgia 2162 children 1000 cases
Children of younger age were at higher risk for MRSA and a relation between MRSA and PVL [4] Kishk et al Patients from hospital in Baltimore, Maryland
36 children With trough concentration of 11mg/L in children, it can be achieved an AUC/MIC>400
[5] Qin et al Pediatric patients from Shenzen Children’s hospital
58 females 82 males 140 cases
There is a predominance of the strain MRSA-ST59-SCCmec IV-t437 in this region, and PVL gene was found on MRSA.
[6] Yoo et al Patients from Asan Medical Center Children’s hospital
46 cases Persistent bacteremia at 48 hours was often seen with less than 10 μg/mL concentration trough of vancomycin. Further investigation required for optimal drug exposure.
[7] Zmantar et al
Children from dental clinic in Monastir, Tunisia
9 cases Lactobacillus plantarum extract was found to have resistance-modifying activity. Required further investigation to find out the active compound responsible for this activity.
18 [8] Correa-Jimenez et al Patients from hospital in Cartagena, Colombia.
276 cases High rate of prevalence of PVL among MRSA and MSSA. Relation lack of PVL and resistance to erythromycin. More PVL cases in older patients [9] Davoodaba di et al Children from kindergartens
345 children CA-MRSA colonization was found in high rates on children. Empirical treatment recommended for these cases.
[10] Demir et al Children from department otolaryngology 24 patients 24 controls
No relation found between toxins of Staphylococcus aureus and otitis media with effusion.
[11]
Doudoulaka kis et al
Patients from tertiary care centers
41 cases Molecular investigation showed PVL on MRSA and MSSA. No resistance to vancomycin was found.
[12] Gijon et al
Children around European centers.
152 children Severe outcome is linked with pneumonia, leukopenia and PVL-positive infections. No relation severity with MRSA prevalence. Relation severity infection with PVL presence. [13] Perez et al Patients from Pediatric Hospital Buenos Aires, Argentina 208 children 136 cases
MRSA found predominant and with persistent bacteremia as clinical outcome. Clindamycin found 9% resistance.
[14] Yu et al Children from North American intensive care units
25 children 13 controls
Relation of alpha toxin and MRSA pneumonia in cases of respiratory viral infection.
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[15] Erami et al
Patients from health care centers in Kashan city, Iran
350 children Found MDRSA among children and some resistance to vancomycin was found. Risk factors for nasal carriage of this strain was identified.
[16] Fritz et al
Children from primary and tertiary centers
183 cases Individual decolonization was found more efficient than household decolonization against infection. But the last one was efficient against subsequent infections [17] Carzino et al Patients from a hospital 41 children 61 samples
When proper prophylaxis is applied, no clinical problem with SCV of Staphylococcus aureus was not found in cystic fibrosis cases. [18] Chadha
et al
Patients from a hospital
50 children Toxins are recognized by the immune system in the case of pulmonary infection.
[19] Lemma et al Patients from hospital, Northwest Ethiopia 400 children 206 cases
High colonization of MRSA strains on HIV patients. [20] Tsai et al Patients from a hospital, Taiwan 90 children 123 cultures
Proved usefulness of BAL as diagnostic tool and therapy guide to CA pneumonia that can be caused by Staphylococcus aureus
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Methods
Literature Search and search strategy
A literature search was conducted using PUBMED, ScienceDirect and MEDLINE databases using key word searches „Staphylococcus aureus “, „children “and „pediatrics “. Restrictions were placed on study date, only publications from the last 10 years. Restrictions on the age of the children, only children from 1 month to 18 years of age were included. No restrictions were placed on the location. Publications in english only were included in the review.
Data Collection
Specific data within the studies retrieved were used to determine the pathology, peculiarities and outcome of Staphylococcus aureus in children. The data analysis was conducted by reading the abstracts of all the articles retrieved during the initial research, then narrowed down using specific keywords. Once focused, it was narrowed, relevant information was retrieved from the full texts and synthesized to summarize the data needed.
Results of search
The systematic review initial electronic search yielded 520 abstracts, of which 65 were identified for further evaluation. Out of those 65 studies, 7 were excluded due to inclusion of adults on their participants during the study. It left 58 studies that after further analysis only 56 were retrieved to be potentially relevant studies. The 2 studies that were excluded due to full texts studies weren’t available, thus it couldn’t get proper information about the study. Therefore, 58 articles were selected and analyzed if more exclusion criteria were found.
Additionally, 36 studies were excluded from the review, because they met one or more of the exclusion criteria. Therefore, a total of 20 studies were included in the systematic review. In 19 out of the 36 studies that were excluded, those studies were duplicated studies, meaning the topic of study is similar to one and another, therefore, only one study was taken out of the theme. 4 studies were letters to the Editor, so not enough information could be taken from it. In another 7 studies, they were case reports of a single patient. And 3 more studies were investigations not related to topic of the systematic literal review of
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Staphylococcus aureus in children. 2 studies were found to be investigations older than 10 years, therefore they were excluded from the review. And additionally, it was excluded 1 study because it was from a textbook.
Finally, a total of 20 studies were accepted and included in this review. The following sections will describe the findings of this evaluation study and address once again that this research is a systematic literal review about the relationship of Staphylococcus aureus in children.
Exclusion criteria
Participants which are older than 18 years old or participants younger than 1 month of age were excluded from the review. Other excluded articles were those focused on unrelated topics and not focusing on the peculiarities of Staphylococcus aureus in children. Case reports were also excluded from the research. Duplicated studies were found during the analysis about similar theme, therefore was excluded from the review and was included just one study about the theme. Another exclusion criteria used was the studies that come from textbooks, popular and periodical magazines or newthesis, as is one of the structural requirements. Additionally, studies that were not in English were excluded from the analysis.
22 Study selection
Potentially relevant studies based on keyboard databases (n=65)
Studies excluded due to inclusion of adults on their participants (n=7)
Potential relevant studies to be included in the review (n=58)
Studies excluded due to not found full and complete text of the
research (n=2) Potential relevant studies to be
included in the review (n=56)
Studies excluded due to one or more exclusion criteria: case report, letter to editor, study not English, duplication, not relevant to the topic, older than 10 years…
(n=36) Potential relevant studies to be
included in the review (n=20)
Final 20 studies were included for literal review
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Results
Most of the studies show a high rate of the strain Methicillin-resistant Staphylococcus aureus among the isolates of Staphylococcus aureus [1, 3, 9, 13]. It shows the natural phenomenon over the years on bacteria when antibiotics are applying on them. This results into a specific and selective pressure or natural selection, where only the survival of the resistant strains bacteria is possible. It was specially discovered that the younger the age in the individual, they were at higher risk of colonization [1, 3], therefore probabilities of infection are more elevated at younger age. This is more remarkable on the cases of HIV patients, where the colonization rates were higher than in healthy children [19]. The places where habitually it would colonize are the anterior nares [3]. This increase the amount of Methicillin-resistant Staphylococcus aureus infection and colonization in the community and it will lead to the changes in the precautions and therapeutically course of action. Though, it was proved that following methods of decolonization like the use of soaps, lotions… was efficient as prevention of potential infections [16].
The clinical outcomes seen in this strain of MRSA are skin and respiratory infections [3, 12, 14, 20]. These infections outcomes can develop to more severity, especially respiratory infections, which its severity is associated with pneumonia, leukopenia and the presence of PVL [12]. Thus, this could be included as risk factors for severity. Regarding pneumonia, there is evidence that certain toxins from Staphylococcus aureus known as alpha toxins play a role during respiratory infection in the presence of viral coinfection [14]. Therefore, this alpha toxin can become a target for treatment, neutralizing the activity of the toxin becomes the aim for the treatment. This become clear once was verified that the immune system acts against those same toxins that play a role on the pathology of the disease. Although, toxins from Staphylococcus aureus might be responsible for inflammatory infections, especially on lower and upper airways, it was demonstrated that toxins don’t play a role in the development of infection in the middle ears [10].
PVL relation with Staphylococcus have been studied through different researches. It has been found that PVL might have a relationship between the strains of Staphylococcus aureus that are Methicillin resistant
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as PVL was highly present [3]. This presence of PVL was found in several different strains of MRSA in different regions, and additionally in less percentage in MSSA [5, 8, 11]. In the study of Gijon et al. is shown the relation of the severity of the clinical outcome with the presence of PVL, but this severity was present despite they were strains of methicillin resistance or susceptibility.
In the study of Correa-Jimenez et al. was found a relationship between the lack of PVL and erythromycin resistance, but further analysis should be made.
Several studies have made profiles of resistance and susceptibility of antibiotics against Staphylococcus aureus. And it shows that there is evidence that the resistance pattern is intrinsically different to according to the origin. The most often drug that the bacteria didn’t show resistance it is Vancomycin, therefore it is declared the most successful drug against the bacteria. Though, it has been seen in the study of Erami et al. it was found a resistance against vancomycin in the 4.3% of the 92 cultures analyzed. This might have been caused due mutations, but further investigation should be made onto this topic. But this also indicates that in every region the susceptibility and resistance might differ.
Additionally, in the study of Kishk et al. demonstrated the dose in children (15 mg/kg every six hours) to achieve an AUC/MIC of 400 in children.
The drugs that commonly showed being ineffective to Staphylococcus aureus through the analysis in resistance patterns were methicillin, cephalotonin, clindamycin and oxacillin [2, 15]. And as well, strains of MDRSA was found and carriage of this strain is increased in patients with antibiotic use in the last 3 months, large number of family members and parental smoking [15].
Conclusions
The prevalence and increased risk of carriage and infection among patients depends on the usage of antibiotics in the last 3 months, as well as the lower social situation and economical. Additionally, the presence of PVL on Staphylococcus aureus indicates an increased severity in the clinical outcome.
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