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

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.

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. Methicillin-resistant 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 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 (SCCmec) 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 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 life-threatening [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 mecA codes for this change [32]. The staphylococcal Cassette Chromosome (SCC) consists of the mec and ccrgene 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 healthcare-associated 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 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 long-term 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;

1. Homogeneous resistance is when each bacterium in the colony has the mecA gene, can synthesize PBP2a, and shows a high degree of methicillin resistance.

2. Heterogeneous resistance is the condition in which high methicillin resistance is found in only one of 106 to 108 bacteria, although all bacteria in the colony carry the mecA gene. It is common in the clinic. The fact that PBP2a expression is not strongly induced in strains carrying normal regulatory genes (mecA, mecR1 and mecl) and its induction is much slower causes some strains to be methicillin-sensitive despite carrying the mecA gene. The high methicillin resistance seen in this type of resistance is in a region outside the mec gene; It is the result of an additional chromosomal mutation defined as chr, which is thought to be located at the hmr locus.

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.