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Methicillin-resistant Staphylococcus aureus (MRSA) refers to 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. 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.[1] Strains unable to resist these antibiotics are classified as methicillin-susceptible S. aureus, or MSSA.

MRSA 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 hospital-acquired 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.

Treatment of MRSA infection is urgent and delays can be fatal.[19]:328 The location and history related to the infection determines

The World Health Organization advocates regulations on the use of antibiotics in animal feed to prevent the emergence of drug-resistant strains of MRSA.[27] MRSA is established in animals and birds.[18]

Treatment

Treatment of MRSA infection is urgent and delays can be fatal.[19]:328 The location and history related to the infection determines 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.[4] The use of concurrent treatment with vancomycin or other beta-lactam agents may have a synergistic effect.[20]:637

Both CA-MRSA and HA-MRSA are resistant to traditional anti-staphylococcal beta-lactam antibiotics, such as cephalexin. CA-MRSA has a greater spectrum of antimicrobial susceptibility to sulfa drugs (like co-trimoxazole (trimethoprim/sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin (for beta-lactam antibiotics, such as cephalexin. CA-MRSA has a greater spectrum of antimicrobial susceptibility to sulfa drugs (like co-trimoxazole (trimethoprim/sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin (for osteomyelitis).[4] MRSA can be eradicated with a regimen of linezolid,[84] though treatment protocols vary and serum levels of antibiotics vary widely from person to person and may affect outcomes.[85] The effective treatment of MRSA with linezolid has been successful[84] in 87% of people. Linezolid is more effective in soft tissue infections than vancomycin.[86][1] This is compared to eradication of infection in those with MRSA treated with vancomycin. Treatment with vancomycin is successful in approximately 49% of people.[1] Linezolid belongs to the newer oxazolidinone class of antibiotics which has been shown to be effective against both CA-MRSA and HA-MRSA. The Infectious Disease Society of America recommends vancomycin, linezolid, or clindamycin (if susceptible) for treating those with MRSA pneumonia.[4] 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.[87]

Vancomycin and teicoplanin are glycopeptide antibiotics used to treat MRSA infections.[88] Teicoplanin is a structural congener of vancomycin that has a similar activity spectrum but a longer half-life.[89] Because the oral absorption of vancomycin and teicoplanin is very low, these agents can be administered intravenously to control systemic infections.[90] 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).[91][92]

Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new strains of the MRSA bacterium have been dubbed vancomycin intermediate-resistant S. aureus (VISA).[93] [94] Linezolid, quinupristin/dalfopristin, daptomycin, ceftaroline, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin.[95] Current guidelines recommend daptomycin for VISA bloodstream infections and endocarditis.[4]

This left vancomycin as the only effective agent available at the time. However, 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.[96] However, 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.[97]

Oxazolidinones such as linezolid became available in the 1990s and are comparable to vancomycin in effectiveness against MRSA. Linezolid resistance in S. aureus was reported in 2001,[98] but infection rates have been at consistently low levels. In the United Kingdom and Ireland, no resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006.[99]

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).[4] Examples of soft-tissue infections from MRSA include ulcers, impetigo, abscesses, and SSIs.[86] In surgical wounds, evidence is weak (high risk of bias) that linezolid may be better than vancomycin to eradicate MRSA SSIs.[1]

MRSA colonization is also found in nonsurgical wounds such as traumatic wounds, burns, and chronic ulcers (i.e.: diabetic ulcer, pressure ulcer, burns, and chronic ulcers (i.e.: diabetic ulcer, pressure ulcer, arterial insufficiency ulcer, venous ulcer). No conclusive evidence has been found about the best antibiotic regimen to treat MRSA colonization.[21]

In skin infections and secondary infection sites, topical mupirocin is used successfully. For bacteremia and endocarditis, vancomycin or daptomycin is considered. For children with MRSA-infected bone or joints, treatment is individualized and long-term. Neonates can develop neonatal pustulosis as a result of topical infection with MRSA.[4] Clindamycin is not approved for the treatment of MRSA infection, but it is still used in children for soft-tissue infections.[4]

Endocarditis and bacteremia

CA-MRSA in h

CA-MRSA in hospitalized patients pneumonia treatment begins before culture results. After the susceptibility to antibiotics is performed, the infection may be treated with vancomycin or linezolid for up to 21 days. If the pneumonia is complicated by the accumulation of pus in the pleural cavity surrounding the lungs, drainage may be done along with antibiotic therapy.[4] People with cystic fibrosis may develop respiratory complications related to MRSA infection. The incidence of MRSA in those with cystic fibrosis increased during 2000 to 2015 by five times. Most of these infections were HA-MRSA. MRSA accounts for 26% of lung infections in those with cystic fibrosis.[100]

There is insufficient evidence to support the use of topical or systematic antibiotics for nasal or extra-nasal MRSA infection.[101]

Bone and joint infections[101]

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 by a case-by-case basis. Antibiotic therapy can last up to 3 months and sometimes even longer.[4]

Infected implants

MRSA infection can oc

MRSA infection can occur associated 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 has occurred over 3 weeks ago, the device may be removed. Antibiotic therapy is used in each instance sometimes long-term.[4]

Central nervous system

Treatment is no

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.[4] Pets can be reservoirs and pass on MRSA to people. In some cases, the infection can be symptomatic and the pet can suffer a 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.[76]

Epidemiology

Worldwide

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.[102]

HA-MRSA

In a US coho

In a US cohort study of 1,300 healthy children, 2.4% carried MRSA in their nose.[103] Bacterial sepsis occurs with most (75%) of cases of invasive MRSA infection.[4] In 2009, there were an estimated 463,017 hospitalizations due to MRSA, or a rate of 11.74 per 1,000 hospitalizations.[104] 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.[105] In 2003, the cost for a hospitalization due to MRSA infection was US$92,363; a hospital stay for MSSA was $52,791.[86]

Infection after surgery is relatively uncommon, but occurs as much as 33% in specific types of surgeries. Infections of surgical sites range from 1% to 33%. MRSA sepsis that occurs within 30 days following a surgical infection has a 15–38% mortality rate; MRSA sepsis that occurs within one year has a mortality rate of around

Infection after surgery is relatively uncommon, but occurs as much as 33% in specific types of surgeries. Infections of surgical sites range from 1% to 33%. MRSA sepsis that occurs within 30 days following a surgical infection has a 15–38% mortality rate; MRSA sepsis that occurs within one year has a mortality rate of around 55%. There may be increased mortality associated with cardiac surgery. There is a rate of 12.9% in those infected with MRSA while only 3% infected with other organisms. SSIs infected with MRSA had longer hospital stays than those who did not.[1]

Globally, MRSA infection rates are dynamic and vary year to year.[106] According to the 2006 SENTRY Antimicrobial Surveillance Program report, the incidence of MRSA bloodstream infections was 35.9 per cent in North America. MRSA blood infections in Latin America was 29%. European incidence was 22.8%. The rate of all MRSA infections in Europe ranged from 50% per cent in Portugal down to 0.8 per cent 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%.[86]

The Centers for Disease Control and Prevention (CDC) estimated that about 1.7 million nosocomial infections occurred in the United States in 2002, with 99,000 associated deaths.[107] 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)[citation needed] MRSA alone was associated with 8% of nosocomial infections reported to the CDC National Healthcare Safety Network from January 2006 to October 2007.[108]

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 area of 3,000 per year.[109]

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.[110] 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.[111]

In a US cohort study of 1,300 healthy children, 2.4% carried MRSA in their noses.[103] There are concerns that the presence of MRSA in the environment may allow resistance to be transferred to other bacteria through phages (viruses that infect bacteria). The source of MRSA could come from hospital waste, farm sewage, or other waste water.[4]

LA-MRSA

Livestock associated MRSA (LA-MRSA) has been observed in Korea, Brazil, Switzerland, Malaysia, India, Great Britain, Denmark, and China.[18]

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,[16] with methicillin then being licensed in England to treat resistant infections. Other reports of MRSA began to be described in the 1970s.[1] Resistance to other antibiotics was documented in some strains of S. aureus. In 1996, vancomycin resistance was reported in Japan.[20]:637 In many countries, outbreaks of MRSA infection were reported to be transmitted between hospitals.[69]:402 The rate had increased to 22% by 1995, and by 1997 the level of hospital S. aureus infections attributable to MRSA had reached 50%.

The first report of community-associated MRSA (CA-MRSA) occurred in 1981, and in 1982, a large outbreak of CA-MRSA occurred among intravenous drug users in Detroit, Michigan.[16] Additional outbreaks of CA-MRSA were reported through the 1980s and 1990s, including outbreaks among Australian Aboriginal populations that had never been exposed to hospitals. In the mid-1990s, scattered reports of CA-MRSA outbreaks among US children were made. While HA-MRSA rates stabilized between 1998 and 2008, CA-MRSA rates continued to rise. A report released by the University of Chicago Children's Hospital comparing two periods (1993–1995 and 1995–1997) found a 25-fold increase in the rate of hospitalizations due to MRSA among children in the United States.[112] In 1999, the University of Chicago reported the first deaths from invasive MRSA among otherwise healthy children in the United States.[16] Additional outbreaks of CA-MRSA were reported through the 1980s and 1990s, including outbreaks among Australian Aboriginal populations that had never been exposed to hospitals. In the mid-1990s, scattered reports of CA-MRSA outbreaks among US children were made. While HA-MRSA rates stabilized between 1998 and 2008, CA-MRSA rates continued to rise. A report released by the University of Chicago Children's Hospital comparing two periods (1993–1995 and 1995–1997) found a 25-fold increase in the rate of hospitalizations due to MRSA among children in the United States.[112] In 1999, the University of Chicago reported the first deaths from invasive MRSA among otherwise healthy children in the United States.[16] By 2004, the genome for various strains of MRSA were described.[113]

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.[114]

A population-based study of the incidence of MRSA infections in San Francisco during 2004–05 demonstrated that nearly one in 300 residents suffered from such an infection in the course of a year and that greater than 85% of these infections occurred outside of the healthcare setting.[115] 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.[116] In a meta-analysis of 31 studies, Cosgrove et al.,[117] concluded that MRSA bacteremia is associated with increased mortality as compared with MSSA bacteremia (odds ratio= 1.93; 95% CI = 1.93 ± 0.39).[118] 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.[119]

In the US, the CDC issued guidelines on October 19, 2006, citing the need for additional research, but declined to recommend such screening.[120] 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 blood-stream infections as reported by hundreds of intensive care units decreased 50–70% from 2001–2007.[121] A separate system tracking all hospital MRSA bloodstream infections found an overall 34% decrease between 2005 and 2008.[121] In 2010, vancomycin was the drug of choice.[4]

Across Europe, based mostly on data from 2013, seven countries (Iceland, Norway, Sweden, the Netherlands, Denmark, Finland, and Estonia, from lowest to highest) had low levels of hospital-acquired MRSA infections compared to the others,[122]:92–93 and among countries with higher levels, significant improvements had been made only in Bulgaria, Poland, and the British Isles.[122]:40

A 1,000-year-old eye salve recipe found in the medieval Bald's Leechbook at the British Library, one of the earliest known medical textbooks, was found to have activity against MRSA in vitro and in skin wounds in mice.[123]

MRSA is frequently a media topic, especially if well-known personalities have announced that they have or have had the infection.[124][125][126] 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.[127] Lawsuits filed against those who are accused of infecting others with MRSA are also popular stories in the media.[128][129]

MRSA is the topic of radio programs,[130] television shows,[131][132]MRSA is the topic of radio programs,[130] television shows,[131][132][133] books,[134] and movies.[135]

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.[136]

The delivery of inhaled antibiotics along with systematic administration to treat MRSA are being developed. This may improve the outcomes of those with cystic fibrosis and other respiratory infections.cystic fibrosis and other respiratory infections.[100] Phage therapy has been used for years in MRSA in eastern countries, and studies are ongoing in western countries.[137][138]

MRSA will be included in experiments and cultured on the International Space Station to observe the effects of zero gravity on its evolution.[139][140]

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.[141]