Section 1 Colonization

## **Chapter 1**

## *Staphylococcus aureus* and Methicillin Resistant *Staphylococcus aureus* (MRSA) Carriage and Infections

*Songul Cetik Yildiz*

## **Abstract**

*Staphylococcus aureus* is among the most common opportunistic infections worldwide, as it is found as part of the flora in many parts of the body. *S. aureus* is the leading cause of nosocomial infections with its ability to rapidly colonize the infected area, high virulence, rapid adaptation to environmental conditions, and the ability to develop very fast and effective resistance even to new generation antibiotics. Methicillin-resistant *Staphylococcus aureus* (MRSA), first identified in the 1960s, is one of the most successful modern pathogens, becoming an important factor in hospitals in the 1980s. MRSA is an important factor, especially in hospitalized patients and healthcare-associated infections. Patients colonized with *S. aureus* and MRSA are at risk for community-acquired infections. It is critical that multidrug resistance reduces treatment options in MRSA infections and MRSA strains. These microorganisms have been the subject of research for years as they spread and become resistant in both social and medical settings and cause great morbidity and mortality. With the rapid spread of resistance among bacteria, antibiotic resistance has increased the cost of health care, and this has become the factor limiting the production of new antibiotics.

**Keywords:** *Staphylococcus aureus*, MRSA, infections, antibiotic resistance

## **1. Introduction**

*Staphylococcus aureus* is the most virulent member of the staphylococcal species. The development of infection depends on the balance between the virulence of the microorganism and the host defence system. *S. aureus* is a versatile, highly adaptive pathogen and is ubiquitous, capable of colonizing the skin and mucous membranes of the anterior nostrils, gastrointestinal tract, perineum, genitourinary tract, and pharynx. *S. aureus* can cause community-acquired and healthcare-associated infections with high morbidity and mortality. It is most commonly isolated from wound infections, urinary tract infections, pneumonia, septic arthritis, osteomyelitis,

endocarditis and sepsis, skin and soft tissue infections, bloodstream infections, and hospital-acquired postoperative wound infections.

*S. aureus*, which is an opportunistic pathogen, has been one of the most frequently isolated pathogens, both from the hospital and from the community, which can lead to more serious infections in the presence of suitable conditions. For the first time in the 1940s, when an *S. aureus* strain developed resistance to penicillin, the development of antibiotic resistance in *S. aureus* was recognized. Methicillinresistant *S. aureus* (MRSA), which is also virulent, also shows multidrug resistance and has all the pathogenic properties of *S. aureus* strains. The feature that provides methicillin resistance in *S. aureus* is associated with PBP2a, which is encoded by the *mecA* gene complex. Detection of *mecA* gene by molecular methods is the gold standard in the detection of methicillin resistance. Accurate detection of methicillin resistance as soon as possible is of great importance in the control, treatment and selection of the right antibiotic for MRSA infections. Attempts to develop a vaccine for MRSA have so far been unsuccessful. Finally, in 2018, the Pfizer multi-antigen vaccine phase IIb trial (2018) was also stopped on the grounds that it was useless.

Treatment of bacterial infections is a major problem due to the development of resistance. The discovery and development of new drugs are of great importance in order to overcome this problem, which significantly weakens the clinical effectiveness of traditional antibiotics. In this review, we aimed to summarize the extensive literature on the epidemiology, transmission, genetic diversity, evolution, surveillance, and treatment of MRSA by providing an overview of basic and clinical MRSA research.

#### **2.** *Staphylococcus aureus*

Gram-positive, non-motile, cocci-shaped, coagulase-positive *S. aureus* is the most clinically important species among 52 species and 28 subspecies in the *Staphylococcus* [1]. The stability and worldwide spread of this pathogen are due to its ability to rapidly acquire and lose determinants of resistance and virulence from other members of the *Staphylococcus* [2]. *S. aureus* is a really hardy bacterium. It is resistant to drying out and it can survive on dry surfaces for a long time. It can survive even at high salt concentrations, providing a basis for selection of the growth medium from other bacteria. They may contain genes responsible for their virulence and resistance to various antibiotics in their chromosomes.

#### **2.1 Pathogenesis of** *S. aureus*

Staphylococci were first described by Robert Koch in 1878 and were reported to cause disease in mice by Alexander Ogston in 1881 [3]. *S. aureus*, the most pathogenic member of staphylococci, is the cause of many life-threatening diseases such as superficial skin abscess, food poisoning, bacteremia, necrotic pneumonia in children and endocarditis [4]. The ability of *S. aureus* to infect is realized by the colonization of the bacteria into the host cells. After birth, the umbilical region, perineal region, nose, and gastrointestinal tract of the newborn are colonized with *S. aureus*, although not frequently [5]. *S. aureus* can be seen mostly in the contact of colonized healthcare personnel with patients or in previously colonized patients. Mechanisms involved in the pathogenesis of these infections; adhesion of bacteria to the host, passage through anatomical barriers, inactivation of phagocytic cells, suppression of the humoral immune system of the relevant host and secretion of toxins. Factors affecting the

Staphylococcus aureus *and Methicillin Resistant* Staphylococcus aureus *(MRSA) Carriage… DOI: http://dx.doi.org/10.5772/intechopen.107138*

formation of infection include the state of the host immune system, the number and virulence of microorganisms, and deterioration of skin and mucosal integrity [6]. In particular, patients using invasive medical devices and those with weakened immune systems are vulnerable to *S. aureus* infections [1]. Bonnal et al. reported that *S. aureus* is the causative agent in 18% of nosocomial bloodstream infections. Catheter-related bloodstream infection was detected in 38.2% of these cases [7]. It has been reported that healthcare-associated bloodstream infections caused by *S. aureus* can be used as a marker for general hand hygiene practices and compliance with infection control measures in hospitals [8].

#### **2.2** *S. aureus* **carriage**

Nasal *S. aureus* carrier is an important source of infection for *S. aureus*, which can be transmitted by contact and airway. Conditions in which skin integrity is impaired such as burns and trauma may be predisposing factors, as well as foreign bodies such as prostheses and catheters are important risk factors. Contagion is also seen with the use of common items such as towels. Contamination is especially high in indoor areas. The reason for the higher rates of carriage in children and young people is stated to be more contact with respiratory secretions in these age groups. There is a strong relationship between nose and hand carriage in *S. aureus* infections.

In a study, when cultures were taken from the nose, perineum, groin, and armpit were compared, *S. aureus* growth was most common in the nose [9]. Although it increases during menstruation, it has been reported that 10% of women of childbearing age have *S. aureus* carriage in the vagina. It has been stated that while there may be different *S. aureus* strains in the same person, 69% of MRSA-positive patients may have colonization in more than one region [10]. *S. aureus* carriers are divided into four persistent, intermittent, transient carriers and non-carriers. While 10–35% of healthy individuals are persistent carriers and 20−75% are intermittent carriers, persistent carriers have a higher risk of developing infection due to the higher bacterial load. Intermittent carriers usually consist of healthcare workers, such as intensive care workers, who become decolonized between two shifts [11]. Persistent carriage is higher in children, and it turns into intermittent carriage between the ages of 10−20 [12]. Carriage is significantly higher in the presence of diabetes mellitus, hemodialysis or peritoneal dialysis patients, intravenous drug users, healthcare workers, inpatients, patients with eczematous skin disease, liver failure, and HIV infection [13].

Nosocomial infections are a global problem of patient loss. While nosocomial infections can occur in 5−10% of hospitalized patients in developed countries, this rate is around 25% in underdeveloped countries [14]. While the cases with *S. aureus* growth in blood culture were 5.5% of all cases, it was determined that 69% of the cases with only *S. aureus* growth consisted of samples obtained from intensive care units [15].

#### **2.3** *S. aureus* **resistance**

While epidemics can be treated easily, some invasive infections such as bacteremia, septic arthritis, toxic shock syndrome, osteomyelitis and endocarditis may trigger, and these conditions may require inpatient treatment due to difficult complications. Antibiotic treatment is recommended against infections caused by pathogen in the body [16]. Clinically, treatment options are limited as *S. aureus* has acquired significant resistance to multiple classes of antibiotics [17]. It has shown significant

potential in rapidly responding to the challenge posed by new antibiotics through the evolution of novel antimicrobial resistance mechanisms. The development of resistance in these pathogens occurs with enzymatic inactivation of the antimicrobial agent, change in the target site of the drug, efflux pump and sequestration of the antimicrobial agent [18].

*S. aureus* has developed resistance to almost all antibiotics that have been in clinical use for centuries as an important health problem for humanity. Antibiotic resistance of *S. aureus*, which started with sulfonamides, extended to glycopeptides. Resistance to penicillins, which came into use in the early 1940s, increased to 50% within five years with the selective selection of penicillinase-producing bacteria, and today it is 95% [19].

Methicillin resistance started to be seen in 1961, two years after it started to be used clinically. Later, resistance development was observed against clindamycin, chloramphenicol, tetracyclines, macrolides, rifampin, aminoglycosides and trimethoprim-sulfomethoxazole antibiotics, which were widely used in the 1970s. Quinolone resistance was detected in the 1980s [6]. Some studies have stated that horizontal gene transfer has a role in the rapid acquisition and spread of antibiotic resistance markers in *S. aureus* [2, 20]. Most of the clinical isolates of *S. aureus* have a plasmid ranging from 1 to 60 kb. These plasmids carry a variable number of resistance genes. Resistance to erythromycin, tetracycline and chloramphenicol is carried by small plasmids, while the larger ones carry multidrug resistance genes against α-lactam, macrolides and aminoglycosides [20]. The development of resistance to β-lactams (penicillin, oxacillin, methicillin and cephalosporin) in *S. aureus* occurs by the acquisition of a genomic island called the staphylococcal cassette chromosome (SCC*mec*) carrying *mecA* [21]. It has been determined that *S. aureus* penicillin resistance develops with the use of penicillin in treatment.

Penicillin resistance is mediated by the *blaZ* gene encoding β-lactamase enzymes [22]. Although penicillinase-resistant antibiotics such as methicillin have been used to overcome penicillin resistance, resistance to methicillin has emerged in *S. aureus* strains. It has been reported that β-lactam antibiotics cannot be used in the treatment of *Staphylococcus* infections due to methicillin resistance. Vancomycin, which is in the glycopeptide group, has been used in MRSA infections. In 2002, vancomycin resistance was also observed in *S. aureus* strains. This has made the treatment of *Staphylococcus* infections difficult [23].

#### **2.4 Diseases caused by** *S. aureus*

Bacteremias caused by staphylococci are examined in two groups hospital and community origin. While bacteremias that start 48−72 hours after hospitalization or within the first 10 days after hospital discharge are hospital-acquired, bacteremias that exist during hospitalization or develop within the first 24−72 hours are community-acquired. *S. aureus* bacteremia is seen at increasing rates in patients with staphylococcal diseases such as osteomyelitis and endocarditis, and in those using established medical devices. Prolonged hospital stays increase bacteremia due to *S. aureus* [6]. *S. aureus* causes common infections such as endocarditis, meningitis, impetigo, folliculitis, carbuncle, furuncle, cellulitis, bacteremia, pericarditis, pneumonia, osteomyelitis and septic arthritis. It also causes toxigenic syndromes such as toxic shock syndrome, septic shock, scalded skin syndrome, food poisoning [24]. It causes furuncle disease in areas where hair follicles are common, such as the face, neck, hips, and armpits [25]. *S. aureus* is one of the major causes of surgical wound

Staphylococcus aureus *and Methicillin Resistant* Staphylococcus aureus *(MRSA) Carriage… DOI: http://dx.doi.org/10.5772/intechopen.107138*

infections. It occurs with the development of edema, erythema and pain around the wound after surgical intervention. In cases where there is no spread to deep tissues, removal of sutures, repetitive dressing and antibiotic treatment are sufficient [6, 10]. Scalded skin syndrome caused by exfoliative toxins produced by *S. aureus* strains and necrotizing pneumonia caused by Panton-Valentine leucocidin toxins can be lifethreatening [26].

#### **3. Methicillin-resistant** *Staphylococcus aureus* **(MRSA)**

Resistance to antibiotics that are not hydrolyzed by β-lactamase is called methicillin resistance. *S. aureus* pathogens have gained methicillin resistance by horizontal transfer of *mecA*, which has low affinity for β-lactam antibiotics and encodes a modified penicillin-binding protein [27]. In MRSA, the acquisition of resistance occurs by mutation of the target gene in the chromosomes, efflux pump system, horizontal transfer of mobile genetic elements (MGEs), or enzymatic action of drugs, as in the case of penicillin [28]. PCR-based methods generally show the best sensitivity, although they have a higher cost and some risk of false-positive results.

#### **3.1 Epidemiology**

With the first use of penicillin in the treatment of staphylococcal infections in 1940, the morbidity and mortality of staphylococcal infections were significantly reduced. However, penicillin-resistant staphylococcal strains were reported for the first time in England in 1944, and many antibiotic resistances were described in staphylococci in the following years.

Staphylococci gain resistance by inhibiting β-lactam antibiotics by hydrolyzing the amide bond of the β-lactam ring with the enzyme β-lactamase (penicillinase) they produce. Methicillin, which is a penicillin derivative and resistant to β-lactamase enzyme, was removed from clinical use due to its serious side effects of causing interstitial nephritis, although it was the first antibiotic produced in 1959 and used in the clinic among β-lactamase antibiotics (methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin) [29]. MRSA spread rapidly in the 1960s and increased in many parts of the world.

The molecular epidemiology of *S. aureus* is largely determined by the succession of regionally dominant strains. Penicillin-resistant phage type 80 or 81 of *S. aureus* increased from 1953 to 1963 [30]. MRSA was identified in 1961, shortly after the introduction of methicillin, and MRSA outbreaks were reported at the same time [31]. Later, towards the end of the 1970s, MRSA infections began to be seen as endemic in Europe and America.

The prevalence of MRSA in the community is increasing due to the epidemic of community-associated MRSA strains. MRSA strains are divided into two groups community-acquired and hospital-acquired. Community-acquired MRSA cases can be seen in people who have not been treated in hospitals, young people, people in crowded communities, athletes and gyms. Community-acquired infections of MRSA usually occur in the form of skin and soft tissue infections.

There are 5 penicillin-binding proteins (PBPs) in methicillin-sensitive *S. aureus* (MSSA) bacteria. There are 7 MRSAs. PBP2a with a weight of 78 kDa is formed by the change of penicillin-binding protein. A gene known as *mec*A codes for this change [32]. The staphylococcal Cassette Chromosome (SCC) consists of the *mec* and *ccr*

gene complexes located near the replication site. Methicillin resistance is caused by the *mec* gene complex [33]. MRSA is formed by the acquisition of a genomic island carrying the methicillin resistance determinant *mecA*. Since its discovery in the UK in the early 1960s, MRSA has been recognized worldwide as the most common cause of human, community and animal-associated infections. Significantly, too many antibiotics with MRSA resulted in a reduction of their therapeutic value, prolonging hospital stays [34].

#### **3.2 MRSA carriage**

The spread of MRSA infection usually occurs in the hospital setting. MRSA infection is carried into the hospital setting by patients or healthcare professionals. When MRSA infection is detected, risk factors such as hospitalization, close contact with a hospitalized person, and a history of chronic disease should be present [23]. MRSA colonization has been detected in nostrils, axillary, rectal, perirectal, oropharyngeal and intestinal samples [35]. Major identified risk factors for MRSA infections include surgery, dialysis, hospitalization, indwelling percutaneous devices such as central venous catheters or feeding tubes, or the patient's previous culture-proven MRSA infection. Healthcare-associated MRSA infection was defined as MRSA infection that developed 48 hours after hospitalization. MRSA is an important factor in healthcareassociated infections, especially in hospitalized patients.

Nasal carriage is important in the epidemiology of MRSA. Studies have indicated that the most suitable area where *S. aureus* bacteria is isolated is the nose. It has been stated that the bacteria are eradicated from other parts of the body in nasal treatment [36]. Almost any material that comes into contact with the skin, such as pens, mobile phones, white coats, and ties, can act as fomite in MRSA transmission. Colonization can continue for a long time. MRSA can also persist in the home setting and complicate eradication attempts [37]. Colonization is not stable as strains have been found to evolve and even migrate within the same host [38]. Nearly 80% of MRSA infections accumulate in the skin and soft tissues and spread rapidly. It has been shown that it causes diseases such as bursitis, osteomyelitis, arthritis, sinusitis, and urinary tract infection due to MRSA infection [39].

Individuals with MRSA colonization or carriers are at risk of developing an infection, and carriers are a source of person-to-person transmission. There are people prone to infection in healthcare facilities. Especially hospitals are areas where the use of antibiotics is high and places where there is frequent contact between people. These conditions facilitate the epidemic spread of MRSA in hospitals.

MRSA is still endemic in many healthcare facilities around the world and has become the focus of global infection control committees. When *S. aureus* strains isolated from hospitalized patients and wound samples were examined in the study, 75% of wound-borne strains, 51% of skin-borne strains and 74% of strains obtained from hospital beds were identified as MRSA. Yüksekkaya et al. stated that 48% of the cases with MRSA in blood culture were isolated from intensive care units, 47% from internal clinics, and 5% from surgical clinics [40]. In the study conducted by Zencir et al. on hospitalized patients, it was reported that 84.6% of the patients with MRSA growth in their blood culture were obtained from the intensive care units and 14.4% from the samples from other clinics [39].

Situations in which MRSA carriage increases include previously acquired MRSA carrier, being an intensive care unit worker, contact with a person carrying MRSA, taking care of a relative in need of home care, acne, chronic inflammatory bowel

Staphylococcus aureus *and Methicillin Resistant* Staphylococcus aureus *(MRSA) Carriage… DOI: http://dx.doi.org/10.5772/intechopen.107138*

disease, contact with pets and raw meat [11]. Because MRSA is both commensal and pathogenic, attempting to eliminate the carrier following detection of MRSA colonization is predictive of the risk of subsequent infection [41].

#### **3.3 Antibiotic resistance of MRSA**

Methicillin resistance is due to the *mecA* gene. *mecA* is a gene encoding a novel penicillin-binding protein that confers resistance to all β-lactam antibiotics, including anti-staphylococcal penicillins, cephalosporins and carbapenems [42]. The emergence of multiple antibiotic resistance in MRSA infections prolongs the treatment period. MRSA infection usually spreads from the hospital [18]. Nosocomial infection is one of the most important factors in the multi-antibiotic resistance of MRSA. Detection of this agent will be an important step in infection control.

Glycopeptide antibiotics are generally preferred in the treatment of MRSA. The commonly preferred vancomycin. Daptomycin, quinopristin-dalfobristin, linezolid, tigecycline are other antibiotics used in the treatment. In a study by Kao et al. it was stated that 98.8% of 470 MRSA bacteria obtained from blood cultures were susceptible to daptomycin [43]. In a study conducted in the USA, it was reported that *S. aureus* bacteria were sensitive to daptomycin at a rate of 99.94% and 53.3% of these were MRSA [44]. In another study, the MRSA strains used were found to be sensitive to linezolid [45]. In a study on 67 MRSA strains, the antibiotics daptomycin, linezolid, teicoplanin, and vancomycin were used. It has been reported that daptomycin has 8 times more effective than vancomycin, 16 times more effect than teicoplanin and 4 times more effect than linezolid [46].

Patients with MRSA infection have higher mortality, longer hospital stays and higher healthcare costs, severe acute renal failure, hemodynamic instability, and longterm ventilator dependence than patients with methicillin-susceptible *Staphylococcus aureus* (MSSA) infection. While there are five penicillin-binding proteins in MSSA strains, a different PBP with a weight of 78 kDa, called PBP2a or PBP2', is additionally synthesized in resistant strains. This protein of different nature exhibits a low affinity for β-lactam antibiotics.

#### *3.3.1 Chromosomal (intrinsic) methicillin resistance*

Chromosomal mutations or deletions in the *mecA* gene system due to frequent or incorrect use of antibiotics may cause the suppressive function to be abolished in *S. aureus* strains and cause continuous production of PBP2a [47].

Chromosomal methicillin resistance occurs in three ways. These;


3.Eagle-tip resistance, strains susceptible to methicillin at low methicillin concentrations become resistant to methicillin at high concentrations. This is presumed to be the result of intact *mecA* regulator genes inducing PBP2a synthesis at high methicillin concentrations [29].

The high prevalence of MRSA is attributed to its toxin production, rapid spread, and capacity to have multiple antibiotic resistance markers. This causes an increasing burden on limited health service. The rapid spread of natural resistance genes among pathogenic strains reduces the clinical importance of many drugs in a short time.

#### **3.4 Treatment**

MRSA causes a challenging, versatile and unpredictable infection. Genetic adaptation capacity and the rapid emergence of strong epidemic strains pose a great threat to health. Studies evaluating genomics, epigenetics, transcription, proteomics, and metabolomics in animal models and patients with a variety of MRSA are crucial to the understanding and treatment of MRSA infection [41]. The hands of hospital staff are important in the spread of MRSA. Recently, methicillin resistance has increased worldwide. The fight against MRSA in the hospital setting is a crucial step in starting the treatment process right away. Immediate initiation of MRSA treatment with early detection will reduce the incidence. In addition to appropriate antimicrobial therapy, infectious disease consultation will reduce mortality from MRSA bacteremia.

An important pathogen in nosocomial infections, MRSA has also gained importance as a community source. The risk of colonization and infection is higher in patients using antibiotics. MRSA is methicillin-resistant and resistant to all β-lactam antibiotics. It is mentioned that there is resistance to clindamycin, macrolides, tetracycline, chloramphenicol and aminoglycosides. Mortality rate in MRSA infections is much higher than in MSSA. Patients infected with MRSA are hospitalized for more time in intensive care treatment. Multiple antibiotics effective against MRSA have been approved by the FDA since 2014. However, the sustained and high mortality rate from invasive MRSA infection suggests the need for high-quality studies to determine the optimal management for these patients. In order to carry out such studies, it is necessary to establish a clinical research network. By expanding the research area, the clinical impact of this pathogen can be reduced.

#### **4. Conclusion**

Hospital infections not only affect the patient but also negatively affect the companions and healthcare workers. Many problems such as an increase in morbidity and mortality, decrease in quality of life, loss in cost and productivity, and prolongation of hospital stay are caused by nosocomial infections. The major challenge in the treatment of *S. aureus* infection is the lack of suitable therapeutic agents, as pathogens develop resistance to almost all antibiotics. The increasing problem of antibiotic resistance in hospital infections caused by MRSA has become an important health problem that increases its severity worldwide. As a result, there is an increase in the rates of healthcare-associated infections caused by *S. aureus* and MRSA. This increase can be prevented by providing adequate training on hygiene, increasing compliance with standard infection control measures, and improving the rational use of antibiotics.

Staphylococcus aureus *and Methicillin Resistant* Staphylococcus aureus *(MRSA) Carriage… DOI: http://dx.doi.org/10.5772/intechopen.107138*

## **Author details**

Songul Cetik Yildiz Department of Medical Services and Techniques, Mardin Artuklu University, Vocational Higher School of Health Services, Mardin, Turkey

\*Address all correspondence to: songulcetik@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 2**

## Multidrug-Resistant *Staphylococcus aureus* as Coloniser in Healthy Individuals

*Asdren Zajmi, Fathimath Shiranee, Shirley Gee Hoon Tang, Mohammed A.M. Alhoot and Sairah Abdul Karim*

### **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.

**Keywords:** *Staphylococcus aureus*, multidrug resistance *S. aureus*, community acquired-MRSA, healthy individuals, antibiotic resistance

### **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, nonspore-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 [5–7]. 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 [8–10], 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 [20–25]. 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 [27–29]. 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]. Multidrugresistant *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 [31–33]. 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 [39–43].

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 [66–69]. 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







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

**Table 1.**

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**.

### **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 *mec*A gene which encodes the PBP2a [85]. Hence, molecular characterisation of *S. aureus* is vital in identifying virulence genes such as Pantonvalentine leucocidin (PVL) and the *mec*A 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 [88–91]. To identify whether an MRSA isolate is communityassociated 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 *mec*A 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 *erm*A and *erm*C are found in *Staphylococcus* resulting in the production of rRNA methylase always (cMLSB) or producing methylase only in the presence of an inducer (iMLSB) 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]. Multidrugresistant *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 multidrugresistant. 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 [111–113]. 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.

## **Author details**

Asdren Zajmi1 \*, Fathimath Shiranee2 , Shirley Gee Hoon Tang3 , Mohammed A.M. Alhoot<sup>2</sup> and Sairah Abdul Karim2

1 Faculty of Health and Life Sciences, Management and Science University, Shah Alam, Selangor, Malaysia

2 Post Graduate Centre, Management and Science University, Shah Alam, Selangor, Malaysia

3 Center for Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia

\*Address all correspondence to: asdren\_zajmi@msu.edu.my

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2
