|Year : 2020 | Volume
| Issue : 2 | Page : 192-199
Prevalence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus nasal carriage and their clonal diversity among patients attending public health-care facilities
Aline Pecanha Muzy Dias1, Lorrayne Cardoso Guimarães2, Livia B. D V. Petrucci3, Jéssica A Z. Pinheiro3, Marcos Gabriel Pinheiro4, Felipe Rodrigues E Silva3, Helvécio C C. Póvoa3, Fábio Aguiar-Alves1
1 Department of Basic Science, Fluminense Federal University, Nova Friburgo; Department of Pharmacy, University Laboratory Rodolpho Albino, Molecular Epidemiology Laboratory; Program of Pathology and Program of Microbiology and Parasitology, Fluminense Federal University, Niterói, RJ-, Brazil
2 Department of Medical Microbiology, Nosocomial Laboratory, Paulo de Goés Microbiology Institute, Rio de Janeiro Federal University, Rio de Janeiro, Brazil
3 Department of Basic Science, Fluminense Federal University, Nova Friburgo, RJ-, Brazil
4 Department of Pharmacy, University Laboratory Rodolpho Albino, Molecular Epidemiology Laboratory, Fluminense Federal University; Program of Pathology and Program of Microbiology and Parasitology, Fluminense Federal University, Niterói, RJ-, Brazil
|Date of Submission||13-Apr-2020|
|Date of Decision||15-Jun-2020|
|Date of Acceptance||20-Jul-2020|
|Date of Web Publication||29-Aug-2020|
Dr. Fábio Aguiar-Alves
Laboratório Universitário Rodolpho Albino, Molecular Epidemiology Laboratory, Rua Dr. Mário Viana, 523, Santa Rosa, Niterói, Rio de Janeiro
Source of Support: None, Conflict of Interest: None
Context: Nosocomial infections arise from many microorganisms, including Staphylococcus aureus. Aims: The aim of this study is to determine the molecular epidemiology of circulating methicillin-resistant S. aureus (MRSA) clones among patients attending community and health-care facilities in Nova Friburgo, RJ, Brazil. Methods: A total of 1002 nasal swab samples were collected from May 2010 to September 2015. S. aureus isolates were identified through phenotypic tests, submitted to antimicrobial susceptibility tests and genotypic analysis to detect mecA, panton-valentine leucocidin (PVL) genes, SCCmec, SPA and multilocus sequencing typing (MLST) typing. Results: We identified 294 (29.3%) isolates as S. aureus and 91 (9.1%) as MRSA. A total of 17 isolates did not present a correlation between phenotypic and genotypic resistance profiles. Among MRSA isolates, 17 (18.7%) carried PVL genes. A total of 20 different SPA types were determined, being grouped by MLST into eight different sequence types. ST5/t002 was the most prevalent genotype found among these isolates. Conclusions: There is a gradual colonisation shift happening in the infection pattern by S. aureus in Brazil. The Brazilian Epidemic Clone (ST239-SCCmec IIIa-PVL-) seems to be substituted by isolates from different clonal complexes, such as ST5, ST8 and ST30. The non-correlation between phenotypic/genotypic resistance profile observed in some isolates suggests the presence of other methicillin resistance mechanisms different from mecA presence or a difference in the nucleotide sequence, which prevents the primers to identify the specific region during polymerase chain reaction reactions. MRSA identification should be based on phenotypic and genotypic testing to ensure the various types of resistance mechanisms.
Keywords: Methicillin resistance, molecular epidemiology, nasal colonisation, Staphylococcus aureus
|How to cite this article:|
Muzy Dias AP, Guimarães LC, V. Petrucci LB, Z. Pinheiro JA, Pinheiro MG, E Silva FR, C. Póvoa HC, Aguiar-Alves F. Prevalence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus nasal carriage and their clonal diversity among patients attending public health-care facilities. Indian J Med Microbiol 2020;38:192-9
|How to cite this URL:|
Muzy Dias AP, Guimarães LC, V. Petrucci LB, Z. Pinheiro JA, Pinheiro MG, E Silva FR, C. Póvoa HC, Aguiar-Alves F. Prevalence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus nasal carriage and their clonal diversity among patients attending public health-care facilities. Indian J Med Microbiol [serial online] 2020 [cited 2020 Sep 18];38:192-9. Available from: http://www.ijmm.org/text.asp?2020/38/2/192/293901
| ~ Introduction|| |
Nosocomial infections are a major concern for public health due to its high rate of mortality in hospitalised patients worldwide. Among various microorganisms causing hospital infections, the high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections in hospitals has been associated with increased patient mortality and healthcare costs.
About 20%–50% of humans are asymptomatic carriers of S. aureus in the nasal cavity., S. aureus carriers are at high risk of infection and a critical means of spreading this organism to others. This species expresses many virulence factors, contributing to the bacteria's3 pathogenicity. Infections by isolates carrying panton-valentine leucocidin (PVL), a cytolytic toxin that affects mononuclear and polymorphonuclear cells, causing necrosis of skin and soft tissues and inflammation, may cause necrotising pneumonia which is often fatal.
The community-acquired MRSA (CA-MRSA) has been usually classified as any strain of MRSA isolated from patients in outpatient clinics or patients with <48 h of hospital admission, with no medical history of infection or colonisation by MRSA or hospitalisation. Most diseases caused by the so-called CA-MRSA worldwide have been associated with five clonal lineages. Most MRSA clones have evolved from five groups of clonal complexes related ancestors having a distinct genotype. Isolates defined as CA-MRSA are associated with >20 different genetic lineages of which five are generally prevalent, including ST1-IV (WA-1, USA400), ST8-IV (USA300), ST30-IV (southwest Pacific clone [SWP]), ST59-V (Taiwan clone) and ST80-IV (European clone).
The surveillance for MRSA infections should include immediate identification of patients who have an increased risk for its acquisition and analysis of isolates by genotypic methods. These measures would contribute to the rapid detection of possible outbreaks of MRSA clones in both hospital and community settings. Thus, this study aims to establish, for the first time, the molecular epidemiology of circulating MRSA clones in Nova Friburgo, a city nearby Rio de Janeiro, Brazil. Furthermore, their antimicrobial resistance profiles among community and health-care units will be equally analysed.
| ~ Methods|| |
The study is in accordance with the ethical standards of the Ethics and Research Committee of the School of Medicine of Fluminense Federal University (CAAE number 00887812.1.0000.5243/protocol number 146.816).
This is a cross-sectional study that included 1002 subjects over 18 years old, attending three public health care units in Nova Friburgo, Rio de Janeiro, Brazil.
Samples were collected from 05/2010 to 11/2012 and 01/2014 to 08/2015 through rotation of dry and sterile swab in the anterior portion of both nostrils of each patient and plated onto mannitol salt agar plates (HiMedia Laboratories Pvt. Limited, Mumbai, India). Colonies suspected of being Staphylococcus spp. were submitted to Gram staining and standard biochemical analysis (catalase, coagulase and DNase testing) to identify S. aureus species. The control strains used in the coagulase tube test (Coagu-plasma®, Laborclin, Pinhais, Brazil) and catalase test were S. aureus INCQS 00015 ATCC 25923 (positive control for both tests) and Staphylococcus epidermidis INCQS 00016, ATCC 12228 (negative control for coagulase test).
S. aureus isolates were subjected to antimicrobial susceptibility disk diffusion testing as recommended by CLSI. A bacterial suspension of each S. aureus isolate adjusted to 0.5 McFarland scale was plated into Mueller-Hinton Agar (HiMedia Laboratories Pvt. Limited, Mumbai, India) plates. Disks of 11 different antimicrobials (Laborclin, Pinhais, Brazil) were added to the plates: cefoxitin (30 μg), clindamycin (2 μg), chloramphenicol (30 μg), ciprofloxacin (5 μg), erythromycin (15 μg), gentamicin (10 μg), nitrofurantoin (300 μg), penicillin (10U), rifampicin (5 μg), sulphamethoxazole-trimethoprim (23.75 μg/1.25 μg) and tetracycline (30 μg). The control strains used were S. aureus INCQS 00015 ATCC 25923 (methicillin-sensitive S. aureus [MSSA]) and S. aureus INCQS 00306 ATCC 33591 (MRSA).
All isolates identified as S. aureus were also subjected to polymerase chain reaction (PCR) to detect the mec A gene  and PVL genes. The control strains used for mec A gene detection were S. aureus INCQS 00015 ATCC 25923 (negative control) and S. aureus INCQS 00306 ATCC 33591 (positive control).
All MRSA isolates were tested by multiplex-PCR for SCCmec typing.
Protein A (SPA) typing  and multilocus sequencing typing (MLST) were performed to determine the clonal lineage of MRSA isolates. PCR products of both tests (SPA and MLST testing) were purified by kit Wizard SV Gel and PCR Clean-up System (Promega Biosciences Inc., Madison, USA) and sequenced in both directions (ABI-Prism 3130, Applied Biosystems). All sequences obtained were reviewed and analysed in SeqMan and EditSeq (DNA Star, Lasergene, Madison, USA). All sequences were submited to the MLST database (http://saureus.mlst.net) for allelic determination (sequence type [ST]) and the Ridom Spa Server for spa type identification (http://spaserver.ridom.de/).
Chi-square test was used to evaluate the correlation between these results and risk factors for MRSA colonization, presented as categorical data, using SPSS 17.0 Statistic program (Armonk, NY, USA). Results were considered statistically significant when P ≤ 0.05.
| ~ Results|| |
A total of 1002 patients were enrolled in the study. Out of them, 71 swab nasal samples were obtained from patients attending a Maternity Hospital (HMNF) (7%), 907 from Municipal Hospital (HMRS) (91%) and 24 from North Polyclinic (2%).
A total of 294 isolates (29.3%) were identified as S. aureus and of these, 91 (9.1%) were classified as MRSA.
Among the MRSA isolates, 76 (7.6% from all collected samples) showed the fragment corresponding to the mec A gene (162pb) as well as phenotypic resistance to cefoxitin by antimicrobial susceptibility disk diffusion test. Four isolates (0.4%) were resistant to cefoxitin; however, the mec A gene has not been detected by PCR. On the other hand, 13 isolates (1.3% from all collected samples and 14.3% from MRSA isolates) presented the mec A gene, while resistance to cefoxitin was not detected (oxacillin-susceptible MRSA [OS-MRSA]).
The OS-MRSA isolates were identified from samples collected in only three Municipal Hospital wards: 76.9% from orthopaedics, 15.4% from internal medicine and 7.7% from haemodialysis [Table 1].
|Table 1: Relationship among sequence types, Spa types, SCCmec, panton-valentine leucocidin genes, antimicrobial susceptibility and phenotypic characteristics in oxacillin-susceptible-methicillin-resistant Staphylococcus aureus isolates|
Click here to view
There were 490 patients that used one type of antimicrobial agent 30 days before data collection, based on the applied questionnaire. Of these, 49 (10%) were colonised by MRSA. There was a statistically significant relationship between the isolation of MRSA and antimicrobial use among patients (P = 0.04). Only eight patients colonised by MRSA who used antibiotics were able to declare the type of antimicrobial agent used.
The antimicrobial resistance observed in the susceptibility testing was: 76.4% for erythromycin, 55.1% for clindamycin, 49.3% for ciprofloxacin, 26.6% for chloramphenicol, 22.5% for tetracycline, 18.6% for sulfamethoxazole-trimethoprim, 8.8% for gentamicin, 9.9% for rifampicin and 8.6% for nitrofurantoin [Table 2].
|Table 2: Relationship among sequence types, Spa types, SCCmec, panton-valentine leucocidin genes and antimicrobial susceptibility in methicillin-resistant Staphylococcus aureus isolates|
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Patients were grouped by age to evaluate its influence on the colonisation by S. aureus and MRSA. The youngest subject was 18 years old and the oldest was 97 years old. There was a statistical significance only between the presence of S. aureus (P = 0.01) and the age group of patients [Figure 1].
|Figure 1: Distribution of the collected samples, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus according to the age of the patients. *P = 0.01|
Click here to view
The highest S. aureus isolation rate was observed among subjects aging between 18 and 28 years old (46 S. aureus in 124 subjects - 47.1%) and lowest among 69–78 year old people (19 S. aureus in 106 subjects - 17.9%). However, MRSA isolation was higher among individuals from 79 to 98 years old (68 subjects, 11 MRSA - 16.2%), and lower among those aging between 18–28 and 39–48 years old, both with 5.6% (seven MRSA isolates in 124 samples collected and nine MRSA in 162 samples, respectively).
PVL genes were detected in 34 (11.6%) S. aureus isolates and 17 were concomitantly positive for mecA and PVL genes (P = 0.01) [Table 2].
The SCCmec typing showed that nine MRSA isolates (9.9%) carried SCCmec I, 32 (35.2%) SCCmec II, six (6.6%) SCCmec III, and 22 (24.2%) SCCmec IV. Only one isolate (1.1%) was characterised as SCCmec type V [Table 2].
The 20 SPA types determined were grouped into eight STs, based on MLST classification. It was not possible to perform MLST identification in 12 isolates. The relationship between ST, SPA and SCCmec types is shown in [Table 2]. OS-MRSA genotypic details are shown separately in [Table 1].
The ST05 was the most prevalent ST with the highest diversity of SPA types among them. The second most prevalent ST was ST08, typed as t008 SCCmec IV and PVL positive [Table 2]. This is the first time ST8 isolates were identified as more prevalent than the other commonly found ST s in Brazil, ST239 and ST30.
OS-MRSA showed great genomic diversity. There were eight different SPA types grouped into five different STs [Table 1]. The ST05 was also the most prevalent ST. PVL genes were detected in two (15.4%) OS-MRSA isolates.
Distribution of ST according to patients' residency districts and the units where the samples were collected shows that ST5 is the most geographically dispersed ST in both cases. The main district, the most populous, presented the greater variety of ST and the highest number of ST5 isolates (24 isolates, 51.8% from this district). ST5 isolates, as well as ST8, were also described in the other two cities in the surrounding of the city of Nova Friburgo.
| ~ Discussion|| |
Antimicrobial resistance is a growing threat to public health care and a major concern worldwide. Increasingly, governments around the world are paying more attention to this serious problem that challenges modern medicine. Although many different microorganisms are responsible for nosocomial infections, MRSA is still one of the main causes of these infections.
In this study, we found three main correlations between MRSA phenotyping and genotyping. The first one is related to the presence of phenotypic and genotypic methicillin resistance (9.1% of all collected samples), which is what is expected. The second regards phenotypic susceptibility to cefoxitin with the presence of the mec A gene, OS-MRSA (1.3% of all collected samples and 14.3% from MRSA isolates). The last one is represented by phenotypically cefoxitin-resistant isolates with a negative PCR reaction for the mec A gene (0.4%). These findings suggest that there were different kinds of methicillin resistance patterns among the isolates identified in this study.
MRSA is defined as S. aureus strains that express mec A or another mechanism of methicillin resistance. These strains are considered resistant to all β-lactam antimicrobial agents, except the newer cephalosporins with anti-MRSA activity.
OS-MRSA was characterised as a new type of MRSA for the first time in 2000's. The majority of clinical laboratories evaluate bacterial antimicrobial susceptibility by disk diffusion assay or through determination of minimum inhibitory concentration, but not the mec A gene detection by PCR. Therefore, patients presenting infections due to OS-MRSA isolates may be treated as if they were caused by MSSA, receiving β-lactam antimicrobial agents that will not actually treat the infection and may increase β-lactam resistance.
A previous study conducted in Brazil assessed phenotypic and genotypically the methicillin susceptibility of 89 S. aureus isolates. The authors observed that about 33% of the isolates were susceptible to cefoxitin, however carried SCCmec elements. In our study, 4.4% of the S. aureus isolates (and 14.3% of the MRSA isolates) presented the same profile. As well as the other study, we noticed a high diversity in MLST and non-typeable SCCmec elements. In our study, 54% of OS-MRSA presented a non-typeable SCCmec, while in the other study, this was observed in 43% of the isolates. These authors suggested the OS-MRSA phenomenon can also occur by partial excision of SCCmec components in multiresistant MRSA isolates or by chromosomal integration of the cassette in MSSA strains containing SCCmec segments.
The transcriptional control of the mec A gene is mediated both directly and indirectly by other unidentified determinants (other than mec RI and mec I complex mec), resulting in the expression of resistance to β-lactams. Thus, these changes would lead to the expression of elements involved in sensitivity to this class of antibiotics, even with the presence of the mec A gene. These observations may explain our findings of resistance without the presence of mec A gene and vice versa.
A total of 4.4% of MRSA isolates (four samples) presented phenotypic resistance to oxacillin/cefoxitin but were not positive for the PCR reaction targeting mec A gene [Table 2].
In 2012, it was described for the first time a divergent gene homologous to the mec A called mec C, present in SCCmec type XI isolates. This variation of the mec A gene is not detected by regularly used primers, presenting PCR negative results. To exclude the presence of mec C gene among these four previously mentioned MRSA isolates, a nucleotide sequencing of the mec region has been performed and all isolates presented mec A homology.
In addition to the β-lactamase and PBP2a, five other proteins (PBP2, PBP4, GdpP, YjbH and AcrB) have been described to be associated with resistance to β-lactams in S. aureus. These strains presenting other types of resistance to β-lactams are known as BORSA (borderline oxacilin-resistant S. aureus)., The resistance in some BORSA isolates is attributed to the presence of overexpression of β-lactamase while in others, is mediated by chromosomal mutations. However, it is also possible to identify negative mec A and mec C samples without overexpression of β-lactamase.,
Based on this variation in phenotypic and genotypic analysis and the already known methicillin resistance mechanisms, the actual detection of MRSA should not be done only by using regular genotypic tests or, much less, only by phenotypic tests, as routinely performed in many clinical laboratories. Other laboratory techniques, like latex agglutination, may be a rapid and specific method to identify MRSA and OS-MRSA. Studies have showed that latex agglutination method, to detect PBP2a, might be proposed as a reliable diagnostic techinique for detection of MRSA isolates in clinical or research laboratories, where molecular methods are limited., Ideally, the combination of both techniques, phenotypic and genotypic, should be performed to avoid misidentifications.
MRSA strains susceptible to non β-lactam antibiotics, generally, grow significantly faster, have different clonal origins, carry small SCCmec (usually SCCmec IV or V), present high expression of virulence factors and harbor PVL encoding genes.
However, the observed results in the present study showed that these strains, originally considered as CA-MRSA, are circulating widely in healthcare environments. Although 89% of MRSA isolates in this study are considered epidemiologically as HA-MRSA, there were no significant relationship between SCCmec type and epidemiological classification. Of all 91 MRSA isolates identified, 22 (24.2%) carried the SCCmec IV, conventionally associated with CA-MRSA. However, of these SCCmec IV isolates, 17 (77.3%) were epidemiologically classified as HA-MRSA representatives.
Strains associated with nosocomial infection outbreaks within community have been described since 2003 in the United States, Israel, Germany, Greece, United Kingdom and Switzerland. These isolates are usually typed as ST30-SCCmec IVc t019 PVL positive, ST5-SCCmec IVa t311 PVL positive, USA300 (ST8, t008, SCCmec IV PVL positive), the SWP clone (ST30-IV), USA100 (t002/ST5) ST72-IV and ST772-V, among others.
In the present study, the presence of PVL genes were assessed in all S. aureus isolates. Of these, 34 (11.6%) were identified as PVL positive, 17 MSSA and 17 MRSA isolates. The presence of these genes is not exclusive to MRSA, as MSSA strains are also reported carrying PVL genes, being frequently involved in skin and soft-tissue infections and necrotizing pneumonia.
Among the risk factors studied, there was statistical significance in only two of them. The first observed risk factor was the use of antimicrobial agents up to 30 days before the time of inclusion.
Although a study in Turkey with about 1800 patients did not demonstrate the use of antibiotics as a risk factor for MRSA, other studies show that recent use of antimicrobial agents in relation to the time of collection acts as a risk factor for MRSA colonisation. The use of antibiotics might be promoting microorganism selection, favoring the increase of resistant strains.
Another risk factor observed was the relationship between the age variation of the patient and MRSA colonisation. Adults over 65, children under 2-year-old and newborns have been already reported as at high risk for MRSA colonization. The highest frequency of MRSA isolation was observed among individuals between 79 and 98 years old and the lowest in individuals from 18 to 48 years old.
Analysing the dispersion of the Sequencing Types, the ST5 was the most dispersed, in both cities as in different ditricts studied. Included in this ST, nine SPA types were identified. The most common was t002 SCCmec types II and IV. In a study conducted in two cities near Nova Friburgo, it was observed that ST5 (t002) and ST30 (t318) were the most prevalent STs in MRSA colonisation samples.
The Brazilian Epidemic Clone (ST239 SCCmec III) have always been described as one of the main circulating clones in the country, along with the USA800/Paediatric clones (ST5, SCCmec IV,) USA100/New York-Japan clone (ST5 SCCmec II), USA400 (ST1 SCCmec IV) and USA1100/Sothwest clone (ST30 SCCmec IVc). ST30 (USA1100) was also recently described as the most common MRSA clone found in nasal colonissation of patients in a hospital in Rio de Janeiro.
In spite of this study, MLST typing and SCCmec typing corroborate this description. Interestingly, the Brazilian Epidemic Clone was not identified in this study.
Another ST found was the ST8-t008-SCCmec IV-PVL positive, characteristic of USA300 clones. This clone, very common in the United States, has been described as virulent and responsible for infections caused by CA-MRSA. The genome of this strain is characterized by containing elements that facilitate and increase dispersion and virulence, as is the case for PVL carriage. In Brazil, this clone is associated with both infections caused by CA-MRSA and HA-MRSA.
| ~ Conclusions|| |
The PVL genes were not exclusively associated with SCCmec IV but were more frequent in MRSA than in MSSA. The non-agreement between the phenotypic and genotypic antimicrobial susceptibility pattern observed in some samples suggests the presence of other types of mechanisms of resistance to methicillin apart from that defined by the mec A gene. Thus, the MRSA identification should be based on phenotypic and genotypic tests in order to detect the various types of resistance. There is a gradual colonization pattern shift of S. aureus clonal lineages in Brazil. The Brazilian Epidemic Clone (ST239-SCCmec IIIa-PVL-) seems to be gradually substituted by ST5, ST8 and ST30 isolates, previously described as CA-MRSA.
Nova Friburgo Municipal Health Secretary, Fluminense Federal University DNA Sequencing platform, Foundation for Research Support of Rio de Janeiro State (FAPERJ), National Research Council (CNPq).
Financial support and sponsorship
Foundation for Research Support of Rio de Janeiro State (FAPERJ), National Research Council (CNPq).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]