Bacterium responsible for difficult-to-treat infections in humans
Methicillin-resistant "Staphylococcus aureus" (MRSA) is a group of gram-positive bacteria that are genetically distinct from other strains of "Staphylococcus aureus". MRSA is responsible for several difficult-to-treat infections in humans. It caused more than 100,000 deaths worldwide attributable to antimicrobial resistance in 2019.
MRSA is any strain of "S. aureus" that has developed (through natural selection) or acquired (through horizontal gene transfer) a multiple drug resistance to beta-lactam antibiotics. Beta-lactam (β-lactam) antibiotics are a broad-spectrum group that include some penams (penicillin derivatives such as methicillin and oxacillin) and cephems such as the cephalosporins. Strains unable to resist these antibiotics are classified as methicillin-susceptible "S. aureus", or MSSA.
MRSA infection is common in hospitals, prisons, and nursing homes, where people with open wounds, invasive devices such as catheters, and weakened immune systems are at greater risk of healthcare-associated infection. MRSA began as a hospital-acquired infection but has become community-acquired, as well as livestock-acquired. The terms HA-MRSA (healthcare-associated or hospital-acquired MRSA), CA-MRSA (community-associated MRSA), and LA-MRSA (livestock-associated MRSA) reflect this.
Signs and symptoms.
In humans, "Staphylococcus aureus" is part of the normal microbiota present in the upper respiratory tract, and on skin and in the gut mucosa. However, along with similar bacterial species that can colonize and act symbiotically, they can cause disease if they begin to take over the tissues they have colonized or invade other tissues; the resultant infection has been called a "pathobiont".
After 72 hours, MRSA can take hold in human tissues and eventually become resistant to treatment. The initial presentation of MRSA is small red bumps that resemble pimples, spider bites, or boils; they may be accompanied by fever and, occasionally, rashes. Within a few days, the bumps become larger and more painful; they eventually open into deep, pus-filled boils. About 75 percent of CA-MRSA infections are localized to skin and soft tissue and usually can be treated effectively.
Risk factors.
A select few of the populations at risk include:
As many as 22% of people infected with MRSA do not have any discernable risk factors.
Hospitalized people.
People who are hospitalized, including the elderly, are often immunocompromised and susceptible to infection of all kinds, including MRSA; an infection by MRSA is called healthcare-associated or hospital-acquired methicillin-resistant "S. aureus" (HA-MRSA).
Generally, those infected by MRSA stay infected for just under 10 days, if treated by a doctor, although effects may vary from person to person.
Both surgical and nonsurgical wounds can be infected with HA-MRSA. Surgical site infections occur on the skin surface, but can spread to internal organs and blood to cause sepsis. Transmission can occur between healthcare providers and patients because some providers may neglect to perform preventative hand-washing between examinations.
People in nursing homes are at risk for all the reasons above, further complicated by their generally weaker immune systems.
Prison inmates and military personnel.
Prisons and military barracks can be crowded and confined, and poor hygiene conditions may proliferate, thus putting inhabitants at increased risk of contracting MRSA. Cases of MRSA in such populations were first reported in the United States and later in Canada. The earliest reports were made by the Centers for Disease Control and Prevention in US state prisons. In the news media, hundreds of reports of MRSA outbreaks in prisons appeared between 2000 and 2008. For example, in February 2008, the Tulsa County jail in Oklahoma started treating an average of 12 "S. aureus" cases per month.
Animals.
Antibiotic use in livestock increases the risk that MRSA will develop among the livestock and other animals that may reside near them; strains MRSA ST398 and CC398 are transmissible to humans. Generally, animals are asymptomatic.
Domestic pets are susceptible to MRSA infection by transmission from their owners; conversely, MRSA-infected pets can also transmit MRSA to humans.
Athletes.
Locker rooms, gyms, and related athletic facilities offer potential sites for MRSA contamination and infection. Athletes have been identified as a high-risk group. A study linked MRSA to the abrasions caused by artificial turf. Three studies by the Texas State Department of Health found the infection rate among football players was 16 times the national average. In October 2006, a high-school football player was temporarily paralyzed from MRSA-infected turf burns. His infection returned in January 2007 and required three surgeries to remove infected tissue, and three weeks of hospital stay.
In 2013, Lawrence Tynes, Carl Nicks, and Johnthan Banks of the Tampa Bay Buccaneers were diagnosed with MRSA. Tynes and Nicks apparently did not contract the infection from each other, but whether Banks contracted it from either individual is unknown. In 2015, Los Angeles Dodgers infielder Justin Turner was infected while the team visited the New York Mets. In October 2015, New York Giants tight end Daniel Fells was hospitalized with a serious MRSA infection.
Children.
MRSA is becoming a critical problem in children; studies found 4.6% of patients in U.S. health-care facilities, (presumably) including hospital nurseries, were infected or colonized with MRSA. Children and adults who come in contact with day-care centers, playgrounds, locker rooms, camps, dormitories, classrooms and other school settings, and gyms and workout facilities are at higher risk of contracting MRSA. Parents should be especially cautious of children who participate in activities where sports equipment is shared, such as football helmets and uniforms.
Intravenous drug users.
Needle-required drugs have caused an increase of MRSA, with injection drug use (IDU) making up 24.1% (1,839 individuals) of Tennessee Hospital's Discharge System. The unsanitary methods of injection causes an access point for the MRSA to enter the blood stream and begin infecting the host. Furthermore, with MRSA's high contagion rate, a common risk factor is individuals who are in constant contact with someone who has injected drugs in the past year.
Mechanism.
Antimicrobial resistance is genetically based; resistance is mediated by the acquisition of extrachromosomal genetic elements containing genes that confer resistance to certain antibiotics. Examples of such elements include plasmids, transposable genetic elements, and genomic islands, which can be transferred between bacteria through horizontal gene transfer. A defining characteristic of MRSA is its ability to thrive in the presence of penicillin-like antibiotics, which normally prevent bacterial growth by inhibiting synthesis of cell wall material. This is due to a resistance gene, "mecA", which stops β-lactam antibiotics from inactivating the enzymes (transpeptidases) critical for cell wall synthesis.
SCC"mec".
Staphylococcal cassette chromosome "mec" (SCC"mec") is a genomic island of unknown origin containing the antibiotic resistance gene "mecA". SCC"mec" contains additional genes beyond "mecA", including the cytolysin gene "psm-mec", which may suppress virulence in HA-acquired MRSA strains. In addition, this locus encodes strain-dependent gene regulatory RNAs known as "psm-mec"RNA. SCC"mec" also contains "ccrA" and "ccrB"; both genes encode recombinases that mediate the site-specific integration and excision of the SCC"mec" element from the "S. aureus" chromosome. Currently, six unique SCC"mec" types ranging in size from 21 to 67 kb have been identified; they are designated types I–VI and are distinguished by variation in "mec" and "ccr" gene complexes. Owing to the size of the SCC"mec" element and the constraints of horizontal gene transfer, a minimum of five clones are thought to be responsible for the spread of MRSA infections, with clonal complex (CC) 8 most prevalent. SCC"mec" is thought to have originated in the closely related "Staphylococcus sciuri" species and transferred horizontally to "S. aureus."
Different SCC"mec" genotypes confer different microbiological characteristics, such as different antimicrobial resistance rates. Different genotypes are also associated with different types of infections. Types I–III SCC"mec" are large elements that typically contain additional resistance genes and are characteristically isolated from HA-MRSA strains. Conversely, CA-MRSA is associated with types IV and V, which are smaller and lack resistance genes other than "mecA".
These distinctions were thoroughly investigated by Collins et al. in 2001, and can be explained by the fitness differences associated with carriage of a large or small SCC"mec" plasmid. Carriage of large plasmids, such as SCC"mec"I–III, is costly to the bacteria, resulting in a compensatory decrease in virulence expression. MRSA is able to thrive in hospital settings with increased antibiotic resistance but decreased virulence – HA-MRSA targets immunocompromised, hospitalized hosts, thus a decrease in virulence is not maladaptive. In contrast, CA-MRSA tends to carry lower-fitness cost SCC"mec" elements to offset the increased virulence and toxicity expression required to infect healthy hosts.
"mecA".
"mecA" is a biomarker gene responsible for resistance to methicillin and other β-lactam antibiotics. After acquisition of "mecA", the gene must be integrated and localized in the "S. aureus" chromosome. "mecA" encodes penicillin-binding protein 2a (PBP2a), which differs from other penicillin-binding proteins as its active site does not bind methicillin or other β-lactam antibiotics. As such, PBP2a can continue to catalyze the transpeptidation reaction required for peptidoglycan cross-linking, enabling cell wall synthesis even in the presence of antibiotics. As a consequence of the inability of PBP2a to interact with β-lactam moieties, acquisition of "mecA" confers resistance to all β-lactam antibiotics in addition to methicillin.
"mecA" is under the control of two regulatory genes, "mecI" and "mecR1". MecI is usually bound to the "mecA" promoter and functions as a repressor. In the presence of a β-lactam antibiotic, MecR1 initiates a signal transduction cascade that leads to transcriptional activation of "mecA". This is achieved by MecR1-mediated cleavage of MecI, which alleviates MecI repression. "mecA" is further controlled by two co-repressors, "blaI" and "blaR1". "blaI" and "blaR1" are homologous to "mecI" and "mecR1", respectively, and normally function as regulators of "blaZ", which is responsible for penicillin resistance. The DNA sequences bound by "mecI" and "blaI" are identical; therefore, "blaI" can also bind the "mecA" operator to repress transcription of "mecA".
Arginine catabolic mobile element.
The arginine catabolic mobile element (ACME) is a virulence factor present in many MRSA strains but not prevalent in MSSA. SpeG-positive ACME compensates for the polyamine hypersensitivity of "S. aureus" and facilitates stable skin colonization, wound infection, and person-to-person transmission.
Strains.
Acquisition of SCC"mec" in methicillin-sensitive "S. aureus" (MSSA) gives rise to a number of genetically different MRSA lineages. These genetic variations within different MRSA strains possibly explain the variability in virulence and associated MRSA infections. The first MRSA strain, ST250 MRSA-1, originated from SCC"mec" and ST250-MSSA integration. Historically, major MRSA clones ST2470-MRSA-I, ST239-MRSA-III, ST5-MRSA-II, and ST5-MRSA-IV were responsible for causing hospital-acquired MRSA (HA-MRSA) infections. ST239-MRSA-III, known as the Brazilian clone, was highly transmissible compared to others and distributed in Argentina, Czech Republic, and Portugal.
In the UK, the most common strains of MRSA are EMRSA15 and EMRSA16. EMRSA16 has been found to be identical to the ST36:USA200 strain, which circulates in the United States, and to carry the SCC"mec" type II, enterotoxin A and toxic shock syndrome toxin 1 genes. Under the new international typing system, this strain is now called MRSA252. EMRSA 15 is also found to be one of the common MRSA strains in Asia. Other common strains include ST5:USA100 and EMRSA 1. These strains are genetic characteristics of HA-MRSA.
Community-acquired MRSA (CA-MRSA) strains emerged in late 1990 to 2000, infecting healthy people who had not been in contact with healthcare facilities. Researchers suggest that CA-MRSA did not evolve from HA-MRSA. This is further proven by molecular typing of CA-MRSA strains and genome comparison between CA-MRSA and HA-MRSA, which indicate that novel MRSA strains integrated SCC"mec" into MSSA separately on its own. By mid-2000, CA-MRSA was introduced into healthcare systems and distinguishing CA-MRSA from HA-MRSA became a difficult process. Community-acquired MRSA is more easily treated and more virulent than hospital-acquired MRSA (HA-MRSA). The genetic mechanism for the enhanced virulence in CA-MRSA remains an active area of research. The Panton–Valentine leukocidin (PVL) genes are of particular interest because they are a unique feature of CA-MRSA.
In the United States, most cases of CA-MRSA are caused by a CC8 strain designated , which carries SCC"mec" type IV, Panton–Valentine leukocidin, PSM-alpha and enterotoxins Q and K, and . The ST8:USA300 strain results in skin infections, necrotizing fasciitis, and toxic shock syndrome, whereas the ST1:USA400 strain results in necrotizing pneumonia and pulmonary sepsis. Other community-acquired strains of MRSA are ST8:USA500 and ST59:USA1000. In many nations of the world, MRSA strains with different genetic background types have come to predominate among CA-MRSA strains; USA300 easily tops the list in the U.S. and is becoming more common in Canada after its first appearance there in 2004. For example, in Australia, ST93 strains are common, while in continental Europe ST80 strains, which carry SCC"mec" type IV, predominate. In Taiwan, ST59 strains, some of which are resistant to many non-beta-lactam antibiotics, have arisen as common causes of skin and soft tissue infections in the community. In