Multidrug-Resistant Staphylococcus aureus as Coloniser in Healthy Individuals

Abstract

Staphylococcus aureus is a common human pathogen that can cause mild superficial infections to deep-seated abscesses and sepsis. One of the characteristics of S. aureus is the ability to colonise healthy individuals while leaving them asymptomatic. These carriers’ risk harbouring an antibiotic-resistant strain that may be harmful to the individual and the community. S. aureus carriage in healthcare personnel is being studied extensively in many parts of the world. However, the relationship between colonisation and disease among those with no previous exposure to healthcare remains untouched. Colonisation of the nasal cavity and its surrounding by pathogenic organisms such as S. aureus leads to the increased risk of infection. Hospital-acquired infections associated with S. aureus infections are common and studies related to these types of infections among various study groups are largely documented. However, over the last decade, an increase in community-associated methicillin-resistant S. aureus has been noted, increasing the need to identify the prevalence of the organism among healthy individuals and assessing the antibiotic resistance patterns. Systemic surveillance of the community for colonisation of S. aureus and identifying the antibiotic-resistant pattern is critical to determine the appropriate empiric antibiotic treatment.

1. Introduction

S. aureus is the most significant pathogen within the genus Staphylococcus and a major human pathogen capable of causing a wide variety of infections [1]. This pathogen was first discovered by a Scottish surgeon from a surgical abscess [2]. S. aureus is a Gram-positive, catalase and coagulase producing, oxidase negative, non-spore-forming cocci [3]. S. aureus can interact with its host as a commensal member of the microbiota [4] or act as an opportunistic pathogen leading to a wide range of community and hospital-associated infections [5, 6, 7]. The nose (anterior nares) is the most frequent ecological niche of S. aureus carriage, but this bacterium can also colonise multiple body sites including pharynx [8, 9, 10], skin, rectum, vagina, axilla, and gastrointestinal tract [11]. It was found that approximately 20–30% of the human population harboured this bacterium persistently and asymptomatically in the anterior nares [4].

Nasal colonisation of S. aureus has shown to be an increased risk factor for the development of community-acquired or nosocomial infections by two to tenfold [12]. Most community-acquired S. aureus infections happen due to autoinfection from anterior nares, skin or both [13]. Transmission of S. aureus may happen through contaminated objects and surfaces although the main route of transmission is mainly from a colonised or individual having an infection with S. aureus [14]. S. aureus is also known to cause mild superficial infections to deep-seated abscesses and life-threatening sepsis [11]. Additionally, it has been documented that persistent nasal colonisation by S. aureus increased the risk for subsequent infections and this situation became even more complicated in immunocompromised and hospitalised individuals which can lead to invasive infections with high morbidity and mortality rates [15, 16].

Antimicrobial resistance has caused a significant challenge to modern medicine as well as to the possibility of effective treatment of infectious diseases. The emergence of antibiotic resistance among S. aureus has been a problem since the identification of penicillinase-producing S. aureus just two years post-discovery of Penicillin [17]. Like other bacteria, S. aureus also develops resistance on exposure to antibiotics, leading to resistant strains [18]. The antibiotic resistance crisis has been accelerated by the misuse and overuse of antibiotics leading to a ‘silent pandemics’ [19]. It has been reported that infections caused by antibiotic-resistant strains of S. aureus have reached epidemic proportions worldwide. Several studies have found that the overall burden of staphylococcal disease in both hospital and community settings, especially that caused by methicillin-resistant S. aureus strains (MRSA), has increased in various countries including China, Brazil, India and Turkey as well as Malaysia [20, 21, 22, 23, 24, 25]. Some previous studies have shown that the emergence of community-associated MRSA (CA-MRSA) strains was one of the major causes of skin and soft-tissue infections [26]. The rapid spread of CA-MRSA strains has been reported in some other countries with a historically low prevalence of MRSA such as Norway, Denmark, Asia, Canada, Australia, Sweden and Finland [27, 28, 29]. CA-MRSA strains have demonstrated a remarkable diversity in the number of different clones that have been characterised [14].

In Asia, the multidrug-resistant strains of S. aureus particularly MRSA have become endemic in most hospitals and poses a major threat to public health and treatment challenge to physicians due to its limited therapeutic options [30]. Multidrug-resistant S. aureus such as MRSA is no longer confined to patients with known risk factors or exposure to healthcare settings. Several reports about MRSA infection have increased the public concerns about the implications of the transmission of S. aureus among healthy individuals. It has been found that MRSA carriage in healthy individuals is a major asymptomatic reservoir that led to the wide spread of MRSA within the community [31, 32, 33]. In Malaysia, a recent study conducted by Suhaili, Azis [34] showed that a total of 49 of S. aureus strains isolated from 200 healthy undergraduate students in the year 2012 and 2013 yielded eight erythromycin-resistant isolates. Among these eight isolates, six were found to harbour the msrA gene and one isolate carried the ermC gene [34].

2. Colonisation

The colonisation of the human body with S. aureus is closely linked with serious blood infections to minor skin infections [35]. The anterior nares happen to be the most common site of S. aureus colonisation with the nasal cavity and vestibule harbouring S. aureus equally [36, 37]. The likelihood of S. aureus being transferred from the nasal site to other body parts via hand transfer is high [38]. Nasal carriage of S. aureus varying from 20% to >50% was detected in studies conducted in different parts of the world [39, 40, 41, 42, 43].

Various other sites colonisation the S. aureus has been documented including the oropharynx, skin, vagina, rectum, gastrointestinal tract and axilla [12]. In a study conducted among healthy individuals in the Iowa United States, nasal swabs and oropharyngeal swabs were collected, revealing a higher prevalence of S. aureus [44]. The authors of this study suggest that the addition of sites other than the anterior nares increases the chances of identifying prevalence rates and genotypic differences among S. aureus in different parts of the body [44]. A study conducted by Azmi, Adnan [45] to identify the prevalence of S. aureus in the oral cavity of healthy adults in Malaysia explained an increase in the occurrence of S. aureus with a significant association with the presence of dental prostheses. With every rise in colonisation, the risk of infection increases, indicating the importance of identifying the different areas and colonisation rates [45]. The colonisation of multiple anatomical sites can lead to horizontal gene transfer and antibiotic resistance between co-colonising strains [46].

S. aureus colonisation rates can vary among individuals with different clinical conditions and having an underlying condition can be a significant factor associated with nasal colonisation [12, 47]. Patients with diabetes mellitus (DM) show a high prevalence of MRSA nasal colonisation [12]. Supportive to this finding are studies conducted by Bhoi, Otta [48] and Lin, Lin [49], where DM patients had a higher rate of MRSA colonisation compared to healthy individuals. This type of colonisation can lead to more severe conditions such as foot ulcers in DM patients [49]. Lin and the team researched diabetic patients in Taiwan to assess the concordance between colonisation and MRSA colonisation, revealing nasal carriage of MRSA to be a significant risk factor for foot ulcers in DM patients [49]. A similar study in New York with patients undergoing total hip arthroplasty and knee arthroplasty showed a high carrier rate of S. aureus [50]. Hidron, Kempker [51] described that an individual’s chance of colonisation with S. aureus is increased by 17% in HIV positive patients and 1.3% - 5.3% in patients admitted in hospital settings [51]. A higher prevalence of S. aureus colonisation (44.0%) was observed among HIV infected individuals in a case-control study done in India [52]. Apart from HIV patients affected with comorbidities such as obesity and diabetes can also have a higher S. aureus carrier rate [12]. A study conducted among the Norwegian population showed a vast increase in S. aureus colonisation with the increase in body mass index (BMI) (for each 2.5 kg/m² a 7% increase) [53]. However, the prevalence rate of S. aureus is not similar to all chronic diseases. S. aureus nasal colonisation rate had no significant difference among rheumatoid arthritis patients and the general population [54].

The prevalence rates of S. aureus in healthy individuals vary from population to population with certain risk factors making them more prone to colonisation [35]. Studies including healthy individuals from the general community or university/college campus in Iran, China, Saudi Arabia and Taiwan showed prevalence rates of 30.16%, 24.7%, 37.0% and 22.0% respectively [40, 41, 43, 55]. Findings from the refugee community indicated a higher prevalence rate of 44.0% in Nepal and 51.2% in Portugal, indicating the variance in prevalence among different populations and geographical distributions [42, 56]. Curry and his team observed that the prevalence of S. aureus colonisation can be increased with living in confined spaces with limited exposure to external environments. This study was conducted among Navy crew members in an assault ship during a 3-week training session. Among the 400 participants, 59.7% was colonised with S. aureus [57]. Prior exposure to antibiotics also poses a risk factor for S. aureus colonisation [58]. A case-control study conducted from 2005 to 2010 revealed that 37% of patients with MRSA infection were exposed to antibiotics three months before [59].

Research conducted among healthy individuals in Malaysia revealed a low prevalence rate of S. aureus from nasal swabs of medical students (9.24%) and dental students (18.0%) [60, 61]. A higher prevalence of S. aureus was observed from oral cavity samples (40.0%) and hand swab samples of food handlers (95.0%) from Ampang Jaya and Klang Valley respectively [45, 62].

3. A pathogen of concern

S. aureus is a fast-evolving Gram-positive coccus and one of the most typical opportunistic pathogens identified [63]. S. aureus has been a leading cause of nosocomial infection till the identification of epidemiologically distinct colonies in community settings [64]. S. aureus is responsible for hospital-acquired infections (HAI) such as surgical site infections, nosocomial pneumonia and central line-associated bloodstream infections (CLABSI) which can lead to life-threatening situations [65]. Several studies and texts describe S. aureus among most common isolates responsible for hospital-acquired infections [66, 67, 68, 69]. With stringent measures, a reduction in HAI with S. aureus is seen but community-acquired infections are still on the rise [70, 71].

S. aureus is frequently isolated from skin and soft tissue infections (SSTIs). A study conducted in Greece from 2014 to 2018 identified the presence of S. aureus in 46.4% of patients with SSTIs [72]. S. aureus was isolated from 62% of all wound or abscess cultures received at a medical treatment facility in the U.S from 2005 to 2010 [73]. Kumar and their team also reported a high percentage of S. aureus (75.0%) isolated from wound abscess of adults and children aged 6 months to 84 years [74]. Apart from SSTIs S. aureus has also been isolated from patients with mastitis. Cultures performed on breast milk from patients with mastitis revealed the presence of S. aureus in 19.8% and 38.2% of the sample from studies conducted in China and Italy respectively [75, 76].

S. aureus infections become more serious when it enters the bloodstream, and this type of infection tends to be more fatal and is regarded as a significant cause of morbidity and mortality in infected patients [77]. Marra, Camargo [78] reported S. aureus as the primary organism responsible for nosocomial bloodstream infections (15.4%) in Brazil with a crude mortality rate of 31.0% [78]. Similar results were also seen in a study conducted with blood samples received from laboratories of 25 European countries where S. aureus was the pathogen in over 3000 samples [79]. Conditions associated with S. aureus bacteraemia such as infective endocarditis and osteomyelitis also remains as important metastatic infections as these can add to the morbidity and mortality rates. An observational study conducted at a Danish hospital included patients admitted with S. aureus bacteraemia (SAB) to determine the prevalence of infective endocarditis among them. The study revealed that 16% of patients with SAB had confirmed infective endocarditis [80]. Also, S. aureus has been reported as the most frequent causative organism (29.4%) in hospitalised patients diagnosed with infective endocarditis in a Canadian study [81].

Numerous studies have demonstrated a significant incidence of S. aureus in healthcare settings that are resistant to antibiotics. There is, however, a significant difference between these studies and those that were carried out in community settings. This is due to the fact that little effort is made at the local level to address the global antibiotic resistance crisis, despite the fact that studies comparing the prevalence of antibiotic resistance in both communities and hospitals all showed consistently high values without a discernible difference. Influenced by many factors including crowded housing, poor cleanliness, inadequate access to healthcare, educational background and contact with asymptomatic MDRSA carriers are all typical causes of community-acquired diseases. Therefore, the evidence of the high incidence of S. aureus antibiotic resistance among healthy individuals from 2016 to 2020 has been prescribed in Table 1.

No.	Author, year	Purpose/Aims/Goals	Approach/Method/Experiment	Dataset/Sampling	Findings/Results
1	(Ahmadi et al., 2019)	Evaluate nasal colonisation of MRSA in healthy individuals	Cross-sectional study; S. aureus isolated from nasal swabs identified by the gram and biochemical testing.; ABST by agar disk diffusion; PCR for mecA, SCCmec, pvl encoding genes	600 randomly chosen individuals based on non-probability haphazard sampling type	High incidence of CA-MRSA in asymptomatic individuals
2	(Abroo et al., 2017)	Investigate prevalence, antimicrobial susceptibility, and molecular characteristics of CA-MRSA	S. aureus cultures identified by gram film & biochemicals. PCR for species-specific genes; ABST by disc diffusion	Nasal swabs of 700 healthy student volunteers	High frequency of S. aureus nasal carriers with multidrug resistance detected
3	(Hanif & Hassan, 2019)	Evaluation of sensitivity value of S. aureus against different antibiotics	S. aureus was identified using gram smear and biochemical testing. ABST by disc diffusion	265 clinical S. aureus isolates from different sources	An increase in an overall antibiotic-resistant trend seen
4	(Eibach et al., 2017)	Identify demographic and season-specific carriage rates, clonal types, virulence markers, and antibiotic susceptibilities of S. aureus isolates	S. aureus from nasal swabs identified by the gram and biochemical testing. ABST by disk diffusion; Spa -typing for virulence testing and PCR for TSST, mec, mecC, mecA	544 children <15 years, nasal swab sample collected on admission	The nasal carriage was dependent on age and season.; Multidrug resistance within S. aureus increased comparatively.
5	(Chen et al., 2016)	Investigate the nasal carriage, molecular characterisation, and antimicrobial resistance of S. aureus in newly admitted inpatients	S. aureus identified based on biochemical testing, molecular identification by identifying nuc gene, ABST by disk diffusion	Nasal swabs from 292 patients 48 hrs within the admission	Nasal colonisation of CA-MRSA and H.A.- MRSA detected with high resistance to erythromycin among S. aureus isolates
6	(Chen et al., 2017)	Determine prevalence and risk factors of S. aureus nasal carriage	Cross-sectional study; Identification of S. aureus by biochemical testing and MRSA by cefoxitin and PCR for mecA, pvl, sea, and seb genes; ABST by disk diffusion; Questionnaire to identify risk	Two hundred ninety-five nasal swabs were taken from university teachers, undergraduates, middle school, salesclerks, and retirees.	Prevalence of S. aureus more likely in males aged 20–30 with irregular nasal cleaning behaviour. Molecular heterogeneity among S. aureus isolates seen
7	(Conceição et al., 2019)	Determine MRSA colonisation rates and significant risk factors for S. aureus carriage, also to characterise S. aureus clonal population, antibiotic resistance, and virulence	MRSA was confirmed by PCR amplification of nuc, mecA, and spa genes. ABST by disk diffusion method.; Characterisation by PFGE, spa typing, MLST, SCCmec typing, and pvl detection	Nasal swabs from 84 individuals >18 years old meeting the eligibility criteria (living without facilities to cook and intact nasal mucosa)	S. aureus colonisation rate was high with low MRSA colonisation together with a pool of highly transmissible ST398-t1451 MSSA lineage
8	(Laub et al., 2018)	Estimate S. aureus nasal carriage rate in healthy children population and characterise strains by molecular techniques	S. aureus was identified by biochemical testing. PCR to detect nucA and mecA gene. ABST performed by MIC method	Nasal swabs of 1390 healthy children (3 to 7) year old from 20 different day-care centres	A high carriage rate of S. aureus was seen in preschool children, but the CA-MRSA carriage rate was low. All MRSA isolates belonged to ST45
9	(Le et al., 2018)	Determine whether analysis of a single S. aureus from an individual is adequate to determine the carrier status of a particular strain or characteristics of S. aureus	Biochemical testing to identify S. aureus. Spa, mecA, and scn gene identified by PCR.; ABST was done by disc diffusion method	19 participants (190 isolates total) were selected from a cohort of industrial hog operation workers and household members	Relying on testing one isolate may not capture the variable characteristics of S. aureus
10	(Ronga et al., 2019)	Evaluate cumulative antibiograms of S. aureus clinical isolates	Biochemical identification and antibiotic susceptibility by VITEK MSTM and VITEK 2 System TM	1229 samples from hospitalised and ambulatory care patients	Higher resistance rates were detected for penicillin, oxacillin, levofloxacin, erythromycin, and clindamycin.; The difference in annual resistance was not statistically significant
11	(Okamo et al., 2016)	Determine the prevalence and antimicrobial susceptibility profile of S. aureus and MRSA and identify the association of S. aureus nasal carriage with demographic and clinical characteristics	Cross-sectional study.; Questionnaire to collect demographic and clinical information. S. aureus identification by gram and biochemical testing. ABST by disk diffusion	Nasal swabs of 314 medical students were randomly selected. Pre-clinical (n = 166) and clinical (n = 148)	High prevalence of S. aureus carriage among medical students with a low prevalence of MRSA
12	(Ansari et al., 2016)	Assess the nasal carriage rate of S. aureus, MRSA and identify antimicrobial susceptibility and associated risk factors	Cross-sectional study. S. aureus was identified by biochemical methods and ABST done using disk diffusion.	The nasal swab of 200 medical students who were not exposed to a clinical setting	No significant association with S. aureus carriage and socio-demographic and habitual risk factors. URTIs can increase the carriage of S. aureus and MRSA
13	(Gong et al., 2017)	Describe the prevalence of S. aureus, its antibiotic resistance, and the presence of mecA and PVL genes	S. aureus was identified by biochemical test and latex agglutination. ABST testing by disk diffusion and strain testing for mecA by PCR	Nasal swabs of 314 healthy Tibetan children living at an altitude of 2500–4100 meters.	Prevalence of S. aureus increasing among the population with detection of methicillin-resistant strains
14	(Wang et al., 2017)	Elucidate the carriage rate of S. aureus and MRSA among competitive sports participants	S. aureus was identified, and ABST was done with disk diffusion. Molecular characterisation was done by PFGE and MLST. A questionnaire was34filled for demographics and risk factors	The nasal swabs of 259 students; 120 non-athletes, and 139 athletes	No significant difference in the nasal carriage of MRSA among athletes and non-athletes. The carriage rate of S. aureus among non-athletes and athletes was the same.
15	(Suhaili et al., 2018)	Assess antimicrobial susceptibility profiles of S. aureus isolated from a healthy population and determine the prevalence of constitutive and inducible clindamycin resistance	S. aureus confirmed with gram and biochemical testing. ABST by disk diffusion and molecular detection of virulence genes and antimicrobial resistance genes by PCR	Nasal swabs of 200 university students in health sciences	The presence of pvl-positive MSSA carriage and MLSB suggest the importance of nasal carriage as a transmission of disease.
16	(Azis et al., 2017)	Assess and compare the antimicrobial susceptibility pattern of S. aureus, also to identify the molecular and methicillin resistance-associated genotypes of S. aureus.	S. aureus was identified by the gram and biochemical testing, ABST by disc diffusion, and E-test. mecA, SCCmec, spa gene identification by PCR	120 university students, nasal swabs collected, and persistent carriers identified (n = 39)	Persistent antimicrobial patterns and limited methicillin resistance-associate genotypes were observed.
17	(Lim Fong et al., 2018)	Prevalence and antibiotic sensitivity profile of S. aureus and MRSA isolates from medical students	Culture and biochemical testing for the identification of S. aureus. Disk diffusion and Brilliance MRSA agar for ABST	60 medical students, 24 preclinical and 36 clinical, nasal swabs collected	High prevalence of S. aureus among medical students and low prevalence of MRSA
19	(Damen et al., 2018)	Determine the prevalence and antibiotic susceptibility of S. aureus nasal carriage among medical laboratory science students	Culture, gram and biochemical tests for identification of S. aureus. Disc diffusion performed for ABST	241 medical laboratory science students. Nasal swabs collected	A high prevalence of S. aureus nasal carriage noted
20	(Dunyach-Remy et al., 2017)	Compare genotypic profile of S. aureus strains isolated from nares and diabetic foot ulcers	Biochemical identification and antibiotic susceptibility of S. aureus by VITEK 2 automated system. Genotyping done with S. aureus genotyping kits	276 patients with diabetic foot ulcers. Nasal swabs and wound swabs collected	A high percentage of the diabetic population harbours the same S. aureus isolate in both wounds and nares.
21	(El Aila et al., 2017)	Prevalence of S. aureus and MRSA carriage among health care workers	Cross-sectional study. Organism identification by culture, gram and biochemical tests. ABST by disk diffusion. mecA gene detection by PCR	200 nasal swabs from health care workers	Nasal carriage of MRSA high among health care workers
22	(Nakamura et al., 2017)	Effect of nasal carriage of S. aureus on surgical site infection (SSI)	Statistical analysis identifying the significance of results	4148 patients screened for nasal bacterial carriage before orthopaedic surgery	Patients with nasal carriage of S. aureus had a higher incidence of SSI than those without.
23	(Walsh et al., 2018)	Determine if there is a specific patient population at increased risk of S. aureus nasal colonisation	Nasal screening is done six weeks before surgery and five days before surgery after chlorhexidine wash. Univariate and multivariate analysis to determine independent risk factors	716 patients undergoing primary or revision total hip arthroplasty (THA) and knee arthroplasty (TKA)	Patients on dialysis and patients with diabetes mellitus had a higher carrier rate of S. aureus
24	(Karabay, 2016)	Investigate and compare the frequency of nasal carriage of S. aureus in preclinical and clinical students	S. aureus identified by culture and biochemical testing. ABST did by disc diffusion	Nasal swabs were taken from 146 medical students; 82 preclinical and 64 clinical students	Frequency of nasal carriage of S. aureus four times higher in clinical than preclinical students
25	(Rampal et al., 2020)	Detect colonisation and contributory factors of MRSA on neckties, headscarves, and I.D. badges among medical students	Cross sectionals study. MRSA was identified using traditional culture and PCR.	251 students participated and 433 swab samples were collected from accessories	A significant association between preclinical vs. clinical medical students and S. aureus colonisation on neckties, headscarves, and ID badges
26	(Albert et al., 2018)	Determine the prevalence of S. aureus nasal colonisation in patients with rheumatoid arthritis (R.A.)	Detection of S. aureus by culturing and biochemical testing	Nasal swabs of 207 patients with rheumatoid arthritis and 37 healthy controls	No significant difference between R.A. patients and the general population in the prevalence of S. aureus nasal colonisation.
27	(Hobbs et al., 2018)	Determine the prevalence and risk factors of S. aureus colonisation and examine the association with the community-	S. aureus identification by culture and MALDI-TOF mass spectrometry. ABST did by disk diffusion	5006 nasal swabs, 4868 oropharyngeal swabs, and 5105 skin swabs from a total of 5126 children	S. aureus colonisation is associated with community-onset of skin and soft tissue infections
		onset of infection
28	(Haque et al., 2016)	Identify the knowledge level of medical students about antibiotic resistance in clinical years of university	Cross-sectional questionnaire-based survey.	164 students studying MBBS in years III, IV, and V	Identified that there is a gap between theoretical input and clinical practice
29	(Huang et al., 2019)	Nasal carriage of MRSA among international conference attendees	Detection of MRSA by PCR and cefoxitin disc. Genotyping and molecular characterisation by PFGE, MLST.	Nasal swabs of 209 conference attendees from 23 countries	MRSA carriage rates were similar to previous studies.
30	(Lin et al., 2020)	Assess the concordance between colonisation and clinical MRSA isolates	S. aureus identified by culture and biochemical testing. ABST by disc diffusion and E-test. For molecular characterisation, PFGE used	Nasal swabs of 354 diabetic patients, 112 with foot ulcer and 242 without foot ulcer	Nasal MRSA carriage is a significant risk factor for foot ulcer MRSA infection
31	(El-Mahdy et al., 2018)	Frequency of S. aureus and predominant clones including MRSA colonisation in the nares of healthy individuals	S. aureus identified by culture and biochemical testing. ABST by disc diffusion and molecular characterisation by PFGE, PCR, and MLST.	Two hundred ten healthy individuals; 70 non-hospitalised adults, 68 clinical students, 72 HCWS. Nasal swabs collected	Higher colonisation rate in the healthy community compared to clinical students and HCWs
32	(Bhoi et al., 2020)	Prevalence and risk factors for MRSA nasal colonisation in diabetic patients	Culture and biochemical testing for the identification of S. aureus. ABST by disc diffusion	Four hundred two patients were diagnosed with diabetes. Nasal swabs collected	Nasal colonisation rate of MRSA higher in diabetes mellitus patients
33	(Wu et al., 2019)	Prevalence of nasal carriage and diversity of MRSA among patients and HCWs	The mecA gene and cefoxitin resistance identify MRSA. ABST by disc diffusion.	Nasal swabs of 204 patients visiting the emergency department and 326 HCWS	Nasal MRSA colonisation was observed in both patients and HCWs
34	(Rasheed & Hussein, 2020)	Prevalence rate and antibiotic sensitivity profile of S. aureus in secondary school students	A cross-sectional community-based study. S. aureus identification by culture and biochemical.	Four hundred ninety-two students were selected based on exclusion criteria. Nasal	A high prevalence of S. aureus with increased antibiotic resistance was seen in the
			testing. ABST by disc diffusion	swabs were collected	selected population.
35	(Azmi et al., 2020)	Prevalence of S. aureus in the oral cavity of healthy adults	A cross-sectional study. Culture and biochemical testing were performed to identify S. aureus.	140 oral rinse samples from healthy individuals	High prevalence of S. aureus in the oral cavity of healthy adults
36	(Seow et al., 2021)	Identify the prevalence of S. aureus and its antimicrobial profile among food handlers	S. aureus was identified and antibiotic susceptibility testing done	200 hand swab samples from food handlers and 100 cooked food samples	Increased prevalence of S. aureus (95%) among food handlers including MDRSA
37	(Hanson et al., 2018)	Determine the prevalence of S. aureus colonisation in the nares and oropharynx of healthy persons and risk factors associated	S. aureus isolated and identified by culturing and biochemical testing. mecA, nuc, and 16S rRNA gene identified by PCR	Nasal and oropharyngeal swabs of 263 participants; 177 adults and 86 minors	Higher prevalence of S. aureus colonisation identified with the addition of oropharyngeal swab and environmental contamination known as the strongly associated risk factor
38	(Oberoi et al., 2020)	Detect inducible clindamycin resistance in nasal carriers of S. aureus	A prospective cross-sectional study. Identification of S. aureus by culture and biochemical testing and ABST by disc diffusion. D-test for detection of inducible clindamycin resistance	Nasal samples of 100 nursing staff and doctors	Increasing incidence of MRSA and inducible clindamycin resistance among health care workers
39	(Carrel et al., 2017)	Emergence and diffusion of clindamycin and erythromycin-resistant MSSA among veterans	A retrospective cohort was conducted to identify MSSA invasive infections. MSSA isolates tested against tetracycline, lincosamides, and macrolides only included	34,025 patient isolates meeting inclusion criteria included	Increase in phenotypic of potential ST398 (resistant to clindamycin and erythromycin but tetracycline susceptible) MSSA
40	(Che Hamzah et al., 2019)	Evaluate susceptibility profiles of MRSA and MSSA and determine the prevalence of inducible clindamycin resistance	ABST testing was performed by disc diffusion. Tigecycline and vancomycin resistance detected by MIC	199 S. aureus strains, 90 MRSA and 109 MSSA	Overall high prevalence of inducible clindamycin resistance and tigecycline resistance seen

Table 1.

Summary of studies on S. aureus isolated from healthy individuals from 2016 to 2020.

4. Antimicrobial resistance patterns

Antibiotic resistance is a huge global threat rising dangerously to a high level. According to the WHO global priority list of antibiotic-resistant bacteria, S. aureus is categorised as a priority 2 or level ‘high’ organism [82]. The emergence of antibiotic resistance among S. aureus dates back to the 1940s during which penicillin-resistant S. aureus was identified [14]. The penicillin-resistant S. aureus expressed a β-lactamase that hydrolysed the β-lactam ring found in antibiotics that target the cell wall [18].

The development of methicillin resistance among S. aureus isolates dates to the 1960s, increasing MRSA in hospital infections and later in community-acquired infections [5, 83]. Resistant to methicillin in S. aureus occurs by the expression of the methicillin-hydrolysing β-lactamase and a foreign penicillin-binding protein (PBP) [84]. The methicillin-resistant S. aureus differs from the methicillin-sensitive S. aureus by the presence of the mecA gene which encodes the PBP2a [85]. Hence, molecular characterisation of S. aureus is vital in identifying virulence genes such as Panton-valentine leucocidin (PVL) and the mecA gene responsible for antibiotic resistance of the organism [86].

The prevalence of MRSA among clinical isolates and community samples still exists [39, 40, 87], but recent studies reveal a decrease in MRSA prevalence specifically in the community [88, 89, 90, 91]. To identify whether an MRSA isolate is community-associated or not molecular testing can be done to identify the presence of the gene SCCmec types IV and V as these two types are the most prevalent among CA-MRSA strains [89]. Similarly, spa typing to identify the spa gene of S. aureus helps in understanding the genetic diversity and clonal relatedness of the isolated organisms [92]. While the spa gene informs us of the presence of S. aureus in the specimen, its occurrence, together with the mecA gene, indicates the presence of MRSA [93]. Likewise, identifying the scn gene can suggest that the organism originated from livestock [94, 95].

With the decrease in the prevalence of MRSA seen in different populations, an increase in resistance to lincosamides and macrolides among S. aureus was identified [34, 96, 97]. Lincosamides are a class of antibiotics containing natural, lincomycin, and semi-synthetic chlorinated derivative clindamycin [98]. These antibiotics act by inhibiting protein synthesis and have good antibacterial activity against Staphylococcus and Streptococcus species and can suppress the expression of virulence factors in S. aureus, therefore, clindamycin is recommended for the treatment of toxin-mediated infections [99]. Macrolides, including erythromycin, are similar to lincosamides as their mechanism of action is by inhibiting protein synthesis and is effective in the treatment of Gram-positive organisms including Staphylococcus species [100]. However, recent studies raise the concern of increased clindamycin and erythromycin resistance seen among S. aureus isolates. S. aureus isolated from various clinical specimens from a hospital in Italy were subjected to antimicrobial susceptibility testing to identify the resistance rates and revealed the increase in resistance to clindamycin in sputum isolates (58.3%) and erythromycin in urine isolates (51.55%) [101]. Resistance to clindamycin is the result of enzymatic methylation of the antibiotic binding site of the ribosomal subunit [99]. The methylase is coded by a variety of erm genes of which ermA and ermC are found in Staphylococcus resulting in the production of rRNA methylase always (cMLS_B) or producing methylase only in the presence of an inducer (iMLS_B) such as erythromycin [102].

A study conducted among school children in Kathmandu, Nepal revealed 23.4% isolates to show inducible resistance to clindamycin [103]. Similarly 15.2% of isolates from clinical specimens from an Iran hospital showed inducible clindamycin resistance [104]. As both antimicrobial groups, namely lincosamides and macrolides, have been used to treat S. aureus infections in Malaysia since 2015 [22], identifying the resistance pattern for these antibiotics is deemed necessary. A study conducted among health care workers of a tertiary hospital in Terengganu, Malaysia, highlighted the increase in the prevalence of inducible clindamycin resistance and tigecycline resistance among MRSA and MSSA isolates from nasal samples of health care workers [105].

5. Multidrug-Resistant S. aureus

Replace S. aureus is known to have the ability to quickly develop resistance to each new antibiotic that is used [106]. Various mechanisms adapted by S. aureus include inactivating the antibiotic, altering the target of antibiotic, use of efflux pumps to reduce the intake of antibiotics and trapping the antibiotic [106]. A bacterium is regarded as a multidrug-resistant organism when it becomes resistant to more than one antibiotic either by having several different resistant genes or a single resistance mechanism providing resistance to more than one antibiotic [107]. Multidrug-resistant S. aureus is a huge problem in hospital settings as well as in the community. For S. aureus when the organism is identified as an MRSA it is regarded as a multidrug-resistant (MDR) to oxacillin or cefoxitin renders the organism non-susceptible to all types of β-lactams, including cephalosporins, penicillin’s, β-lactamase inhibitors and carbapenems [108]. Increased resistance to antibiotics was identified among MRSA strains in a study conducted in Taiwan and China [109]. Three hundred and thirty-two strains of MRSA were included from the two countries which showed increased resistance to chloramphenicol (43%) and trimethoprim-sulfamethoxazole (89.0%). A study conducted in India with 783 strains of S. aureus from different clinical specimens revealed 301 (38.4%) MRSA out of which 72.1% were multidrug-resistant. Among these MDR strains, 136 were resistant to more than three antimicrobial groups.

Apart from methicillin resistance in S. aureus, resistance to agents such as linezolid’s, vancomycin and teicoplanin and daptomycin has also been reported [110]. Vancomycin-resistant S. aureus (VRSA) strains have now been documented globally since the first clinical isolate was discovered in 1997 [111, 112, 113]. The VRSA prevalence increased by 3.5 times between the years before to 2006 and 2020, from 2% in the pre-2006 period to 5% in the 2006–2014 period to 7% in the post–2015 period [114].

6. Conclusion

This chapter offers more proof of the significant incidence of multidrug-resistant S. aureus in community settings, coming from healthy human sources. These findings should motivate those involved in health research, medicine, advocacy organisations, and health policymakers to collaborate in order to create effective solutions to address this growing global health problem. In order to stop the spread of resistance, it is urgently advised that community-level methods similar to those used in clinical settings, such as monitoring, awareness-raising, improved sanitation and hygiene, prompt disease diagnosis, and strict prescription regulations, be put into place.