Methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for difficult-to-treat infections in humans. It may also be referred to as multiple-resistant Staphylococcus aureus or oxacillin-resistant Staphylococcus aureus (ORSA). The organism is often sub-categorized as Community-Associated MRSA (CA-MRSA) or Hospital-Associated MRSA (HA-MRSA) depending upon the circumstances of acquiring disease, based on current data that these are distinct strains of the bacterial species.

MRSA is a resistant variation of the common bacterium Staphylococcus aureus. It has evolved an ability to survive treatment with beta-lactam antibiotics, including penicillin, methicillin, and cephalosporins. MRSA is especially troublesome in hospital-associated (nosocomial) infections. In hospitals, patients with open wounds, invasive devices, and weakened immune systems are at greater risk for infection than the general public. Hospital staff who do not follow proper sanitary procedures may transfer bacteria from patient to patient.

Discovery and history
MRSA/Multidrug Resistant Staphylococcus aureus was discovered in 1961 in the UK. It is now found worldwide. MRSA is often referred to in the press as a "superbug."

In the past decade or so the number of MRSA infections in the United States has increased significantly. A 2007 report in Emerging Infectious Diseases, a publication of the Centers for Disease Control and Prevention (CDC), estimated that the number of MRSA infections treated in hospitals doubled nationwide, from approximately 127,000 in 1999 to 278,000 in 2005, while at the same time deaths increased from 11,000 to more than 17,000. Another study led by the CDC and published in the October 17 2007 issue of the Journal of the American Medical Association estimated that MRSA would have been responsible for 94,360 serious infections and associated with 18,650 hospital stay-related deaths in the United States in 2005. These figures suggest that MRSA infections are responsible for more deaths in the U.S. each year than AIDS.

The UK Office for National Statistics reported 1,629 MRSA-related deaths in England and Wales during 2005, indicating a MRSA-related mortality rate half the rate of that in the United States for 2005, even though the figures from the British source were explained to be high because of "improved levels of reporting, possibly brought about by the continued high public profile of the disease" during the time of the 2005 United Kingdom General Election.

It has been argued that the observed increased mortality among MRSA-infected patients may be the result of the increased underlying morbidity of these patients. 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 Staphylococcus aureus (MSSA) bacteremia.

While the statistics suggest a national epidemic growing out of control, it has been difficult to quantify the degree of morbidity and mortality attributable to MRSA. A 2004 study showed that patients 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 patients 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% CI = 1.93±0.39). In addition, Wyllie et al. report a death rate of 34% within 30 days among patients infected with MRSA, a rate similar to the death rate of 27% seen among MSSA-infected patients.

Clinical presentation and concerns
S. aureus most commonly colonizes the anterior nares (the nostrils), although the respiratory tract, opened wounds, intravenous catheters, and urinary tract are also potential sites for infection. Healthy individuals may carry MRSA asymptomatically for periods ranging from a few weeks to many years. Patients with compromised immune systems are at a significantly greater risk of symptomatic secondary infection.

According to Betsy McCaughey, founder of the Committee to Reduce Infection Deaths, MRSA can be detected by swabbing the nostrils of patients and isolating the bacteria found inside. Combined with extra sanitary measures for those in contact with infected patients, screening patients admitted to hospitals has been found to be effective in minimizing the spread of MRSA at the Veterans Affairs hospital in Pittsburgh and in hospitals in Denmark, Finland, and the Netherlands.

Many people who are symptomatic present with pus-filled boils and occasionally with rashes.

In the United States and Canada, the Centers for Disease Control and Prevention issued guidelines on 19 October 2006, citing the need for additional research, but declined to recommend such screening.

About 75 percent of CA-MRSA infections are localized to skin and soft tissue and usually can be treated effectively; however CA-MRSA strains display enhanced virulence, spreading more rapidly and causing illness much more severe than traditional HA-MRSA infections, which can affect vital organs and lead to widespread infection (sepsis), toxic shock syndrome and necrotizing ("flesh-eating") pneumonia. This is thought to be due to toxins carried by CA-MRSA strains, such as PVL and PSM. It is not known why some healthy people develop CA-MRSA skin infections that are treatable whereas others infected with the same strain develop severe infections or die.

A new type of drug-resistant staph infection is showing up primarily in gay and bisexual men. It is resistant to even more antibiotics than other MRSA

CA-MRSA often results in abscess formation that requires incision and drainage. Before the spread of MRSA into the community, abscesses were not considered contagious because it was assumed that infection required violation of skin integrity and the introduction of staphylococci from normal skin colonization. However, newly emerging CA-MRSA is transmissible (similar, but with very important differences) from Hospital-Associated MRSA. CA-MRSA is less likely than other forms of MRSA to cause cellulitis.

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, including to sulfa drugs, tetracyclines, and clindamycin. HA-MRSA is resistant even to these antibiotics and often is susceptible only to vancomycin. Newer drugs, such as linezolid (belonging to the newer oxazolidinones class), may be effective against both CA-MRSA and HA-MRSA.

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 (t½). Because the oral absorption of vancomycin and teicoplanin is very low, these agents must be administered intravenously to control systemic infections. Treatment of MRSA infection with vancomyin can be complicated, due to its inconvenient route of administration. Moreover, many clinicians believe that the efficacy of vancomycin against MRSA is inferior to that of anti-staphylococcal beta-lactam antibiotics against MSSA.

Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new evolutions of the MRSA bacterium have dubbed vancomycin intermediate-resistant Staphylococcus aureus (VISA). Linezolid, quinupristin/dalfopristin, daptomycin, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin. MRSA infections can be treated with oral agents, including linezolid, rifampicin+fusidic acid, rifampicin+fluoroquinolone, pristinamycin, co-trimoxazole (trimethoprim-sulfamethoxazole), doxycycline or minocycline, and clindamycin.

On 18 May 2006, a report in Nature identified a new antibiotic, called platensimycin, that had demonstrated successful use against MRSA.

An entirely different and promising approach is phage therapy (e.g., at the Eliava Institute in Georgia ), which has a reported efficacy against up to 95% of tested Staphylococcus isolates.

It has been reported that maggot therapy to treat MRSA infection has been successful. Studies in diabetic patients reported significantly shorter treatment times than those achieved with standard treatments.

Inmates in Prisons
In confined environments, like jails and prisons, with the rotating in and out of a new population that is typically in poor health, there have been a growing number of challenges reported. In February 2008, The Tulsa County Jail in Oklahoma started treating an average of twelve Staph cases per month.

Prevention and infection-control strategies
Alcohol has been proven to be an effective surface sanitizer against MRSA. Quaternary ammonium can be used in conjunction with alcohol to extend the longevity of the sanitizing action. The prevention of nosocomial infections involves routine and terminal cleaning. Non-flammable Alcohol Vapor in Carbon Dioxide systems (NAV-CO2) do not corrode metals or plastics used in medical environments and do not contribute to antibacterial resistance.

In healthcare environments, MRSA can survive on surfaces and fabrics, including privacy curtains or garments worn by care providers. Complete surface sanitation is necessary to eliminate MRSA in areas where patients are recovering from invasive procedures. Testing patients for MRSA upon admission, isolating MRSA-positive patients, decolonization of MRSA-positive patients, and terminal cleaning of patients' rooms and all other clinical areas they occupy is the current best practice protocol for nosocomial MRSA.

At the end of August 2004, after a successful pilot scheme to tackle MRSA, the UK National Health Service announced its Clean Your Hands campaign. Wards will be required to ensure that alcohol-based hand rubs are placed near all beds so that staff can hand wash more regularly. It is thought that if this cuts infection by just 1%, the plan will pay for itself many times over.

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 was employed by all UK hospitals until the mid 1990s, all patients 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 patients are discharged back into the community and then readmitted: when the number of colonised patients 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.

Current US guidance does not require workers in general workplaces (not healthcare facilities) with MRSA infections to be routinely excluded from going to work.

Unless directed by a healthcare provider, exclusion from work should be reserved for those with wound drainage that cannot be covered and contained with a clean, dry bandage and for those who cannot maintain good hygiene practices. Workers with active infections should be excluded from activities where skin-to-skin contact is likely to occur until their infections are healed. Healthcare workers should follow the Centers for Disease Control and Prevention's Guidelines for Infection Control in Health Care Personnel.

To prevent the spread of staph or MRSA in the workplace, employers should ensure the availability of adequate facilities and supplies that encourage workers to practice good hygiene; that surface sanitizing in the workplace is followed; and that contaminated equipment and surfaces are cleaned with detergent-based cleaners or Environmental Protection Agency (EPA)-registered disinfectants.

Reports reflect a nationwide epidemic of MRSA in the US — one that has significantly increased over the past seven years. A 2007 report in Emerging Infectious Diseases, a publication of the Centers for Disease Control and Prevention, estimated that the number of MRSA infections treated in hospitals doubled nationwide, from approximately 127,000 in 1999 to 278,000 in 2005, while at the same time deaths increased from 11,000 to more than 17,000.

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. In the United States, 95 million 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 patients required hospitalization.

Cystic fibrosis patients are often treated with multiple antibiotics, which must be administered in a hospital setting. Frequent hospital visits can increase exposure to MRSA, potentially increasing the rate of life-threatening MRSA pneumonia in this group. The risk of cross-colonization has led to the increased use of isolation protocols among these patients. In a hospital setting, patients who have received fluoroquinolones are more likely to become colonized with MRSA; this is probably because many circulating strains of MRSA are fluoroquinolone resistant, which means that MRSA is able to colonize patients whose normal skin flora have been cleared of non-resistant S. aureus by fluoroquinolones.

In the United States, there have been increasing numbers of reports of outbreaks of MRSA colonization and infection through skin contact in locker rooms and gymnasiums, even among healthy populations. A study published in the New England Journal of Medicine linked MRSA to the abrasions caused by artificial turf. Three studies by the Texas State Department of Health found that the infection rate among football players was 16 times the national average. In December of 2007, a high school football player died from MRSA-infected turf burns. MRSA has also been found in the public school systems throughout the country.

MRSA is also becoming a problem in pediatric settings, including hospital nurseries. A 2007 study found that 4.6% of patients in U.S. health care facilities were infected or colonized with MRSA. A 2008 study indicated that MRSA may be a sexually transmitted disease among gay men. The research found that sexually active gay men in San Francisco are 13 times more likely to be infected than their heterosexual neighbors. Similar trends have been identified in Boston and Los Angeles.

MRSA causes as many as 20% of Staphylococcus aureus infections in populations that use intravenous drugs. These out-of-hospital strains, or CA-MRSA, are more easily treated, though more virulent, than HA-MRSA. CA-MRSA apparently did not evolve de novo in the community but represents a hybrid between MRSA that spread from the hospital environment and strains that were once easily treatable in the community. Most of the hybrid strains also acquired a factor that increases their virulence, resulting in the development of deep-tissue infections from minor scrapes and cuts, as well as many cases of fatal pneumonia.

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. Staphylococcus bacteria account for almost half of all UK hospital infections. The issue of MRSA infections in hospitals has recently been a major political issue in the UK, playing a significant role in the debates over health policy in the United Kingdom general election held in 2005.

On January 6, 2008, half of 64 non-Chinese cases of Methicillin-resistant Staphylococus aureus (MRSA) infections in Hong Kong in 2007 were Filipino domestic helpers. Ho Pak-leung, professor of microbiology, University of Hong Kong traced the cause from high use of antibiotics. In 2007, there were 166 community cases in Hong Kong compared with 8,000 hospital-acquired MRSA (155 recorded cases — 91 involved Chinese locals, 33 Filipinos, 5 each for Americans and Indians, and 2 each from Nepal, Australia, Denmark and England).

Strains
In the UK, the most common strains of MRSA are EMRSA15 and EMRSA16. EMRSA16 is the best described epidemiologically; it originated in Kettering, England, and the full genomic sequence of this strain has been published. EMRSA16 has been found to be 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. Under the new international typing system, this strain is now called MRSA252. It is not entirely certain why this strain has become so successful, whereas previous strains have failed to persist. One explanation is the characteristic pattern of antibiotic susceptibility. Both the EMRSA15 and EMRSA16 strains are resistant to erythromycin and ciprofloxacin. It is known that Staphylococcus aureus can survive intracellularly, and these are precisely the antibiotics that best penetrate intracellularly; it may be that these strains of S. aureus are therefore able to exploit an intracellular niche.

In the United States, most cases of CA-MRSA are caused by a CC8 strain designated ST8:USA300, which carries mec type IV, Panton-Valentine leukocidin, PSM-alpha and enterotoxins Q and K, and ST8:USA400. Other community-associated strains of MRSA are ST8:USA500 and ST59:USA1000.

Laboratory diagnosis
Diagnostic microbiology laboratories and reference laboratories are key for identifying outbreaks of MRSA. New rapid techniques for the identification and characterization of MRSA have been developed. These techniques include Real-time PCR and Quantitative PCR and are increasingly being employed in clinical laboratories for the rapid detection and identification of MRSA strains.