Methicillin-resistant Staphylococcus aureus

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 can be treated effectively. == Risk factors ==

A select few of the populations at risk include: • People with indwelling implants, prostheses, drains, and catheters • People with weak immune systems (HIV/AIDS, lupus, or cancer patients; transplant recipients; severe asthmatics; primary immune deficiencies, etc.) • People with diabetes mellitus • People who inject intravenous drugs • Regular contact with someone who has injected drugs in the past year • People who use fluoroquinolone antibiotics • Elderly people • People who spend time in confined spaces with other people, including occupants of homeless shelters, prison inmates, and military recruits in basic training • People who ingest unpasteurized milk 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. Prison inmates and military personnel Prisons and military barracks 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. 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. 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. with injection drug use (IDU) making up 24.1% (1,839 individuals) of Tennessee Hospital's Discharge System. The unsanitary methods of injection cause an access point for the MRSA to enter the bloodstream 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 the 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. SCCmec Staphylococcal cassette chromosome mec (SCCmec) is a genomic island of unknown origin containing the antibiotic resistance gene mecA. SCCmec 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-mecRNA. SCCmec also contains ccrA and ccrB; both genes encode recombinases that mediate the site-specific integration and excision of the SCCmec element from the S. aureus chromosome. SCCmec is thought to have originated in the closely related Mammaliicoccus sciuri species and transferred horizontally to S. aureus. Different SCCmec genotypes confer different microbiological characteristics, such as different antimicrobial resistance rates. Different genotypes are also associated with different types of infections. Types I–III SCCmec are large elements that typically contain additional resistance genes and are characteristically isolated from HA-MRSA strains. MRSA can 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. 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. The DNA sequences bound by mecI and blaI are identical; SpeG-positive ACME compensates for the polyamine hypersensitivity of S. aureus and facilitates stable skin colonization, wound infection, and person-to-person transmission. Strains , which are essential for cell wall synthesis and thus for bacterial life, by permanently binding to their active sites. Some forms of MRSA, however, express a different PBP that will not allow the antibiotic into its active site. Acquisition of SCCmec in methicillin-sensitive S. aureus (MSSA) gives rise to several 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 SCCmec and ST250-MSSA integration. EMRSA16 is identical to the ST36:USA200 strain, which circulates in the United States, and to carry the SCCmec type II, enterotoxin A and toxic shock syndrome toxin 1 genes. These strains are genetic characteristics of HA-MRSA. Community-acquired MRSA (CA-MRSA) strains emerged in the late 1990s to 2000, infecting healthy people who had not been in contact with healthcare facilities. and genome comparison between CA-MRSA and HA-MRSA, which indicate that novel MRSA strains integrated SCCmec into MSSA separately on its own. and ST1:USA400. 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. 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 a remote region of Alaska, unlike most of the continental U.S., USA300 was found only rarely in a study of MRSA strains from outbreaks in 1996 and 2000, as well as in surveillance from 2004 to 2006. A MRSA strain, CC398, is found in intensively reared production animals (primarily pigs, but also cattle and poultry), where it can be transmitted to humans as LA-MRSA (livestock-associated MRSA). == Diagnosis ==

showing MRSA resistant to an oxacillin disk Diagnostic microbiology laboratories and reference laboratories are key to identifying MRSA outbreaks. Normally, a bacterium must be cultured from blood, urine, sputum, or other body-fluid samples, and in sufficient quantities to perform confirmatory tests early on. Still, because no quick and easy method exists to diagnose MRSA, initial treatment of the infection is often based on "strong suspicion" and techniques by the treating physician; these include quantitative PCR procedures, which are employed in clinical laboratories to detect and identify MRSA strains quickly. Another common laboratory test is a rapid latex agglutination test that detects the PBP2a protein. PBP2a is a variant penicillin-binding protein that imparts the ability of S. aureus to be resistant to oxacillin. Microbiology Like all S. aureus (also abbreviated SA at times), methicillin-resistant S. aureus is a gram-positive, spherical (coccus) bacterium about 1 micron in diameter. It does not form spores, and it is not motile. It is frequently found in grape-like clusters or chains. Unlike methicillin-susceptible S. aureus (MSSA), MRSA is slow-growing on a variety of media and has been found to exist in mixed colonies of MSSA. The mecA gene, which confers resistance to several antibiotics, is always present in MRSA and usually absent in MSSA; however, in some instances, the mecA gene is present in MSSA but is not expressed. Polymerase chain reaction (PCR) testing is the most precise method for identifying MRSA strains. Specialized culture media have been developed to better differentiate between MSSA and MRSA, and, in some cases, such media can be used to identify specific strains resistant to different antibiotics. == Prevention ==

Screening In health-care settings, isolating those with MRSA from those without the infection is one method to prevent transmission. Rapid culture and sensitivity testing and molecular testing identify carriers and reduce infection rates. It is especially important to test patients in these settings since 2% of people are carriers of MRSA, even though in many of these cases the bacteria reside in the nostril and the patient will not present any symptoms. MRSA can be identified by swabbing the nostrils and isolating the bacteria. Combined with extra sanitary measures for those in contact with infected people, swab screening people admitted to hospitals is effective in minimizing the spread of MRSA in hospitals in the United States, Denmark, Finland, and the Netherlands. Handwashing The Centers for Disease Control and Prevention offers suggestions for preventing the contraction and spread of MRSA infection, which apply to those in community settings, including incarcerated populations, childcare center employees, and athletes. To prevent the spread of MRSA, the recommendations are to wash hands thoroughly and regularly using soap and water or an alcohol-based sanitizer. Additional recommendations are to keep wounds clean and covered, avoid contact with other people's wounds, avoid sharing personal items such as razors or towels, shower after exercising at athletic facilities, and shower before using swimming pools or whirlpools. Isolation Excluding medical facilities, current US guidance does not require workers with MRSA infections to be routinely excluded from the general workplace. The National Institutes of Health recommend that those with wound drainage that cannot be covered and contained with a clean, dry bandage and those who cannot maintain good hygiene practices be reassigned, Workers with active infections are excluded from activities where skin-to-skin contact is likely to occur. To prevent the spread of staphylococci or MRSA in the workplace, employers are encouraged to make available adequate facilities that support good hygiene. In addition, surface and equipment sanitizing should conform to Environmental Protection Agency-registered disinfectants. Before the patient is cleared from isolation, it is advised that there is dedicated patient-care or single-use equipment for that particular patient. If this is not possible, the equipment must be properly disinfected before it is used on another patient. Public health considerations Mathematical models describe one way in which a loss of infection control can occur after measures for screening and isolation seem to be effective for years, as happened in the UK. In the "search and destroy" strategy that all UK hospitals employed until the mid-1990s, all hospitalized people with MRSA were immediately isolated, and all staff were screened for MRSA and were prevented from working until they had completed a course of eradication therapy that was proven to work. Loss of control occurs because colonised people are discharged back into the community and then readmitted; when the number of colonised people in the community reaches a certain threshold, the "search and destroy" strategy is overwhelmed. One of the few countries not to have been overwhelmed by MRSA is the Netherlands: an important part of the success of the Dutch strategy may have been to attempt eradication of carriage upon discharge from hospital. Decolonization As of 2013, no randomized clinical trials had been conducted to understand how to treat nonsurgical wounds that had been colonized, but not infected, with MRSA, Mupirocin 2% ointment can be effective at reducing the size of lesions. A secondary covering of clothing is preferred. As shown in an animal study with diabetic mice, the topical application of a mixture of sugar (70%) and 3% povidone-iodine paste is an effective agent for the treatment of diabetic ulcers with MRSA infection. Agriculture The World Health Organization advocates regulations on the use of antibiotics in animal feed to prevent the emergence of drug-resistant strains of MRSA. MRSA is established in animals and birds. == Treatment ==

Antibiotics Treatment of MRSA infection is urgent, and delays can be fatal. The location and history related to the infection determine the treatment. The route of administration of an antibiotic varies. Antibiotics effective against MRSA can be given by IV, oral, or a combination of both, and depend on the specific circumstances and patient characteristics. The effective treatment of MRSA with linezolid has been successful Ceftaroline, a fifth-generation cephalosporin, is the first beta-lactam antibiotic approved in the US to treat MRSA infections in skin and soft tissue or community-acquired pneumonia. Vancomycin and teicoplanin are glycopeptide antibiotics used to treat MRSA infections. Teicoplanin is a structural congener of vancomycin that has a similar activity spectrum but a longer half-life. Because the oral absorption of vancomycin and teicoplanin is very low, these agents can be administered intravenously to control systemic infections. Treatment of MRSA infection with vancomycin can be complicated, due to its inconvenient route of administration. Moreover, the efficacy of vancomycin against MRSA is inferior to that of anti-staphylococcal beta-lactam antibiotics against methicillin-susceptible S. aureus (MSSA). Several newly discovered MRSA strains show antibiotic resistance even to vancomycin and teicoplanin. Strains with intermediate (4–8 μg/ml) levels of resistance, termed glycopeptide-intermediate S. aureus (GISA) or vancomycin-intermediate S. aureus (VISA), began appearing in the late 1990s. The first identified case was in Japan in 1996, and strains have since been found in hospitals in England, France, and the US. The first documented strain with complete (>16 μg/ml) resistance to vancomycin, termed vancomycin-resistant S. aureus (VRSA), appeared in the United States in 2002. In 2011, a variant of vancomycin was tested that binds to the lactate variation and also binds well to the original target, thus reinstating potent antimicrobial activity. Linezolid, quinupristin/dalfopristin, daptomycin, ceftaroline, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin. Current guidelines recommend daptomycin for VISA bloodstream infections and endocarditis. but infection rates have been at consistently low levels. In the United Kingdom and Ireland, no linezolid resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006. Skin and soft-tissue infections In skin abscesses, the primary treatment recommended is removal of dead tissue, incision, and drainage. More information is needed to determine the effectiveness of specific antibiotics therapy in surgical site infections (SSIs). In surgical wounds, evidence is weak (high risk of bias) that linezolid may be better than vancomycin to eradicate MRSA SSIs. There is insufficient evidence to support the use of topical or systemic antibiotics for nasal or extra-nasal MRSA infection. Bone and joint infections Cleaning the wound of dead tissue and draining abscesses is the first action to treat the MRSA infection. Administration of antibiotics is not standardized and is adapted on a case-by-case basis. Antibiotic therapy can last up to 3 months and sometimes even longer. Infected implants MRSA infection can occur in association with implants and joint replacements. Recommendations on treatment are based upon the length of time the implant has been in place. In cases of a recent placement of a surgical implant or artificial joint, the device may be retained while antibiotic therapy continues. If the placement of the device occurred over 3 weeks ago, the device may be removed. Antibiotic therapy is used in each instance, sometimes long-term. Central nervous system MRSA can infect the central nervous system and form a brain abscess, subdural empyema, and spinal epidural abscess. Excision and drainage can be done along with antibiotic treatment. Septic thrombosis of cavernous or dural venous sinus can sometimes be a complication. Other infections Treatment is not standardized for other instances of MRSA infection in a wide range of tissues. Treatment varies for MRSA infections related to: subperiosteal abscesses, necrotizing pneumonia, cellulitis, pyomyositis, necrotizing fasciitis, mediastinitis, myocardial, perinephric, hepatic, and splenic abscesses, septic thrombophlebitis, and severe ocular infections, including endophthalmitis. Pets can be reservoirs and pass on MRSA to people. In some cases, the infection can be symptomatic, and the pet can develop an MRSA infection. Health departments recommend that the pet be taken to the veterinarian if MRSA infections keep occurring in the people who have contact with the pet. == Epidemiology ==

Worldwide, an estimated 2 billion people carry some form of S. aureus; of these, up to 53 million (2.7% of carriers) are thought to carry MRSA. S. aureus was identified as one of the six leading pathogens for deaths associated with resistance in 2019 and 100,000 deaths caused by MRSA were attributable to antimicrobial resistance. HA-MRSA (healthcare-associated) In a US cohort study of 1,300 healthy children, 2.4% carried MRSA in their nose. Bacterial sepsis occurs with most (75%) of cases of invasive MRSA infection. Many of these infections are less serious, but the Centers for Disease Control and Prevention (CDC) estimate that there are 80,461 invasive MRSA infections and 11,285 deaths due to MRSA annually. In 2003, the cost for a hospitalization due to MRSA infection was US$92,363; a hospital stay for MSSA was $52,791. According to the 2006 SENTRY Antimicrobial Surveillance Program report, the incidence of MRSA bloodstream infections was 35.9% in North America. MRSA blood infections in Latin America were 29%. European incidence was 22.8%. The rate of all MRSA infections in Europe ranged from 50% in Portugal down to 0.8% in Sweden. Overall, MRSA infection rates varied in Latin America: Colombia and Venezuela combined had 3%, Mexico had 50%, Chile 38%, Brazil 29%, and Argentina 28%. The estimated incidence is 4.5 nosocomial infections per 100 admissions, with direct costs (at 2004 prices) ranging from $10,500 (£5300, €8000 at 2006 rates) per case (for bloodstream, urinary tract, or respiratory infections in immunocompetent people) to $111,000 (£57,000, €85,000) per case for antibiotic-resistant infections in the bloodstream in people with transplants. With these numbers, conservative estimates of the total direct costs of nosocomial infections are above $17 billion. The reduction of such infections forms an important component of efforts to improve healthcare safety. (BMJ 2007) MRSA alone was associated with 8% of nosocomial infections reported to the CDC National Healthcare Safety Network from January 2006 to October 2007. The British National Audit Office estimated that the incidence of nosocomial infections in Europe ranges from 4% to 10% of all hospital admissions. As of early 2005, the number of deaths in the United Kingdom attributed to MRSA has been estimated by various sources to lie in the range of 3,000 per year. In the United States, an estimated 95 million people carry S. aureus in their noses; of these, 2.5 million (2.6% of carriers) carry MRSA. A population review conducted in three U.S. communities showed the annual incidence of CA-MRSA during 2001–2002 to be 18–25.7/100,000; most CA-MRSA isolates were associated with clinically relevant infections, and 23% of people required hospitalization. CA-MRSA (community-associated) In a US cohort study of 1,300 healthy children, 2.4% carried MRSA in their noses. While sharing of isolates can occur, infections in humans seem to originate from HA-MRSA rather than from pet-acquired CA-MRSA. LA-MRSA (livestock-associated) In 2004, MRSA was first isolated on a Dutch pig farm leading to further investigations of livestock associated MRSA (LA-MRSA). Livestock associated MRSA (LA-MRSA) has been observed in Korea, Brazil, Switzerland, Malaysia, India, Great Britain, Denmark, and China. == History ==

In 1961, the first known MRSA isolates were reported in a British study, and from 1961 to 1967, infrequent hospital outbreaks occurred in Western Europe and Australia, with methicillin then being licensed in England to treat resistant infections. Other reports of MRSA began to be described in the 1970s. In 1999, the University of Chicago reported the first deaths from invasive MRSA among otherwise healthy children in the United States. The observed increased mortality among MRSA-infected people arguably may be the result of the increased underlying morbidity of these people. Several studies, however, including one by Blot and colleagues, that have adjusted for underlying disease still found MRSA bacteremia to have a higher attributable mortality than methicillin-susceptible S. aureus (MSSA) bacteremia. A population-based study of MRSA infection incidence in San Francisco during 2004–05 demonstrated that nearly one in 300 residents had such an infection in a year and that more than 85% of these infections occurred outside the healthcare setting. A 2004 study showed that people in the United States with S. aureus infection had, on average, three times the length of hospital stay (14.3 vs. 4.5 days), incurred three times the total cost ($48,824 vs. $14,141), and experienced five times the risk of in-hospital death (11.2% vs 2.3%) than people without this infection. In a meta-analysis of 31 studies, Cosgrove et al., concluded that MRSA bacteremia is associated with increased mortality as compared with MSSA bacteremia (odds ratio= 1.93; 95% ). In addition, Wyllie et al. report a death rate of 34% within 30 days among people infected with MRSA, a rate similar to the death rate of 27% seen among MSSA-infected people. In the US, the CDC issued guidelines on October 19, 2006, citing the need for additional research, but declined to recommend such screening. According to the CDC, the most recent estimates of the incidence of healthcare-associated infections that are attributable to MRSA in the United States indicate a decline in such infection rates. Incidence of MRSA central line-associated bloodstream infections as reported by hundreds of intensive care units decreased 50–70% from 2001 to 2007. A separate system tracking all hospital MRSA bloodstream infections found an overall 34% decrease between 2005 and 2008. and among countries with higher levels, significant improvements had been made only in Bulgaria, Poland, and the British Isles. == In the media ==

MRSA is frequently a media topic, especially if well-known personalities have announced that they have or have had the infection. Word of outbreaks of infection appears regularly in newspapers and television news programs. A report on skin and soft-tissue infections in the Cook County jail in Chicago in 2004–05 demonstrated MRSA was the most common cause of these infections among those incarcerated there. Lawsuits filed against those who are accused of infecting others with MRSA are also popular stories in the media. MRSA is the topic of radio programs, television shows, books, and movies. == Research ==

Various antibacterial chemical extracts from various species of the sweetgum tree (genus Liquidambar) have been investigated for their activity in inhibiting MRSA. Specifically, these are: cinnamic acid, cinnamyl cinnamate, ethyl cinnamate, benzyl cinnamate, styrene, vanillin, cinnamyl alcohol, 2-phenylpropyl alcohol, and 3-phenylpropyl cinnamate. The delivery of inhaled antibiotics along with systemic administration to treat MRSA is being developed. This may improve the outcomes of those with cystic fibrosis and other respiratory infections. Host-directed therapeutics, including host kinase inhibitors, as well as antimicrobial peptides are under study as adjunctive or alternative treatment for MRSA. A 2015 Cochrane systematic review aimed to assess the effectiveness of wearing gloves, gowns, and masks to help stop the spread of MRSA in hospitals; however, no eligible studies were identified for inclusion. The review authors concluded that there is a need for randomized controlled trials to be conducted to help determine if the use of gloves, gowns, and masks reduces the transmission of MRSA in hospitals. ==See also==