HISTORY Bacteriologist Professor Patricia Jevons discovers first Methicillin-resistant Staphylococcus aureas (MRSA) in 1961.October 2nd 1960 was the day when Professor Patricia Jevons observed Staphylococcus aureus that was resistant to the antibiotic Methicillin. This new drug, also known as the chemical compound BRL 1241, had been published in the British Medical Journal as a suitable alternative to Penicillin for resistant strains of Staphylococcus aureus just a month beforehand (September 3rd 1960).

There was some caution reserved in the publication with resistance being shown in lower doses of the drug. Shortly after in February 1961 the British Medical Journal cited Professor Jevons observation of the resistant pathogen that we now know as MRSA.It soon became endemic in UK hospitals and around the world. Now we are seeing its spread in the wider community. With much more virulent strains of other "superbugs" evolving we wonder what the next 50 years will bring.

50 years ago Margaret Patricia Jevons, of the Public Health Laboratory Service in Colindale, London, published the first description of meticillin-resistant Staphylococcus aureus (MRSA). This serendipitous discovery was not without controversy. Meticillin, a semi-synthetic penicillin, was introduced in 1959 to treat penicillinase-producing Staphylococcus aureus infections, which had emerged almost as soon as penicillin was first used. There was no room to add a meticillin disc to the susceptibility-testing plate so, to save money, susceptibility was tested on the phage-typing plate. This agarose plate was incubated at 30°C, which was fortunate because the initial MRSA strains were heterogeneously resistant—ie, most of the MRSA population could express meticillin resistance only at this lower temperature. These MRSA had been missed in the clinical laboratories, where testing was performed at 37°C

WHAT IS MRSA ? Methicillin-resistant Staphylococcus aureus (MRSA) infection is caused by a

strain of staph bacteria that's become resistant to the antibiotics commonly used to treat ordinary staph infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several difficult-to-treat infections in humans. It is also called oxacillin-resistant Staphylococcus aureus (ORSA).

MRSA is any strain of Staphylococcus aureus that has developed, through the process of natural selection, resistance to beta lactam antibiotics, which include the penicillin's (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporin's.

Strains unable to resist these antibiotics are classified as methicillin-sensitive Staphylococcus aureus, or MSSA. The evolution of such resistance does not cause the organism to be more intrinsically virulent than strains of S. aureus that have no antibiotic resistance, but resistance does make MRSA infection more difficult to treat with standard types of antibiotics and thus more dangerous.

Drug resistance occurs because microbes, such as staph bacteria, need to reproduce to ensure their survival. When this ability is threatened, as when they are exposed to antibiotics, microbes adapt and evolve to overcome the block to their reproduction. This can occur naturally, and microbes become genetically altered in ways which allow them to survive in the presence of antimicrobial drugs. However, drug resistance adaptations can be accelerated by human actions, particularly by the overuse and inappropriate use of antibiotics. The escalating use of antimicrobials in humans, animals, and agriculture is increasing the problem of drug resistance.

HOW DOES METHICILLIN RESISTANCE DEVELOP?

Drug resistance occurs because microbes, such as staph bacteria, need to reproduce to ensure their survival. When this ability is threatened, as when they are exposed to antibiotics, microbes adapt and evolve to overcome the block to their reproduction.This can occur naturally, and microbes become genetically altered in ways which allow them to survive in the presence of antimicrobial drugs.

The staph bacterium continues to evolve and is beginning to show resistance to additional antibiotics. In 2002 the first staph strains were found that are resistant to vancomycin, an antibiotic that is one of the few available treatments used as a last resort against MRSA. Although vancomycin-resistant staph strains are currently still quite rare, it is feared that these strains will become more widespread over time and further reduce the limited number of antibiotics that are effective against MRSA.

GENETICSStructure of the staphylococcal cassette chromosome mec, with the recombinase genes complex upstream of the mec complex.

The mec complex contains the mecA gene responsible for β-lactam resistance in Staphylococcus aureus.PBP-2- Penicillin binding protein

IS1272 = insertion sequence-like element;ccrA and ccrB = cassette chromosome recombinase genes A and B that mobilize the mec element;mecR1 = mec sensor transducer and repressor genes that regulate production of PBP-2A, which is responsible for β-lactam resistance

IS431 = integrated plasmid that encodes tetracycline resistance; and orfx = open reading frame in which the mobile elements (staphylococcal cassette chromosome) are located.

Although S. aureus has been causing infections (staph infections) probably as long as the human race has existed, MRSA has a relatively short history. MRSA was first noted in 1961, about two years after the antibiotic methicillin was initially used to treatS. aureus and other infectious bacteria.

The resistance to methicillin was due to a penicillin-binding protein coded for by a mobile genetic element termed the methicillin-resistant gene (mecA). In recent years, the gene has continued to evolve so that many MRSA strains are currently resistant to several different antibiotics such as penicillin, oxacillin, and amoxicillin(Amoxil, Dispermox, Trimox).

HA-MRSA are often also resistant to tetracycline (Sumycin), erythromycin(E-Mycin, Eryc, Ery-Tab, PCE, Pediazole, Ilosone), and clindamycin (Cleocin). In 2009, research showed that many antibiotic-resistant genes and toxins are bundled and transferred together to other bacteria, which speed the development of toxic and resistant strains of MRSA. S. aureus is sometimes termed a superbug because of its ability to be resistant to several antibiotics.

WHAT IS MRSA INFECTION?

MRSA is a bacterium that enters the skin through open wounds to cause septicaemia and is extremely resistant to most antibiotics. This organism is known for causing skin infections in addition to many other types of infections. There are other designations in the scientific literature for these bacteria according to where the bacteria are acquired by patients, such as community-acquired MRSA (also termed CA-MRSA or CMRSA), hospital-acquired or health-care-acquired MRSA (also termed HA-MRSA or HMRSA), or epidemic MRSA (EMRSA).

Statistical data suggest that as many as 19,000 people per year have died from MRSA in the U.S.; data supplied by the CDC in 2011 suggest this number has declined by about 54% from 2005 to 2011, in part, because of prevention practices at hospitals and home care.

In addition, hospital deaths from MRSA infection have declined by about 9,000 per year from 2005-2011. However, the CDC recently estimated about 80,000 infections with 11,000 deaths occurred in 2011, but they suggest that a far greater number of minor infections occurred in both the community and in hospitals.

WHAT CAUSES MRSA?

Garden-variety staph are common bacteria that can live in our bodies.

Plenty of healthy people carry staph without being infected by it. In fact,

one third of everybody has staph bacteria in their noses.

But staph can be a problem if it manages to get into the body, often

through a cut.

Once there, it can cause an infection. Staph is one of the most common

causes of skin infections in the U.S. Usually, these are minor and don't

need special treatment. Less often, staph can cause serious problems like

infected wounds or pneumonia.

Staph can usually be treated with antibiotics. But over the decades, some

strains of staph -- like MRSA -- have become resistant to antibiotics that

once destroyed it. MRSA was first discovered in 1961. It's now resistant to

methicillin, amoxicillin, penicillin, oxacillin, and many other antibiotics.

While some antibiotics still work, MRSA is constantly adapting.

Researchers developing new antibiotics are having a tough time keeping

up.

The symptoms of MRSA depend on where you're infected. Most often, it causes mild infections on the skin, like sores or boils. But it can also cause more serious skin infections or infect surgical wounds, the bloodstream, the lungs, or the urinary tract.

Though most MRSA infections aren't serious, some can be life-threatening. Many public health experts are alarmed by the spread of tough strains of MRSA. Because it's hard to treat, MRSA is sometimes called a "super bug."

Skin and soft tissue MRSA infectionsBoils and abscessesAn MRSA skin infection usually first develops as a painful bump or a mark in the skin that looks like an insect bite. The bacteria often enter the skin through a cut, graze or a hair follicle. This develops into a painful, pus-filled swelling (boil).Some people have additional symptoms, such as a high temperature and a general feeling of being unwell.In some cases, MRSA can cause a larger, pus-filled lump to develop underneath the skin. This is known as an abscess.

CellulitisMRSA contracted outside hospitals or care homes (called community-associated MRSA or CA-MRSA) is much rarer but often causes more extensive skin infections, including a type of infection called cellulitis.Cellulitis is a bacterial infection of the deeper layers of skin and the layer of fat and soft tissues underneath the skin. The main symptom is the skin suddenly turning red, painful, hot and swollen.

If the MRSA bacteria penetrate deeper inside your body or into your blood, they can cause serious infections.Signs that you may have an invasive infection include:a high temperature (fever) of 38C (100.4F) or abovechills,a general sense of feeling unwell ,dizziness,confusion,muscular aches and pain, swelling and tenderness in the affected body part

Invasive MRSA infections can lead to the following conditions:Blood poisoning (sepsis) - which could lead to septic shock, where your blood pressure drops to a dangerously low levelUrinary tract infection - infection of the parts of the body used to take urine out of the body, such as the bladderEndocarditis- infection of the lining of the heartPneumonia - a lung infectionSeptic bursitis - inflammation of bursa (small fluid-filled sacs under the skin) caused by a bacterial infectionSeptic arthritis- inflammation of a joint caused by a bacterial infectionOsteomyelitis - a bone infection caused by bacteria

Invasive MRSA infections

DIAGNOSIS

DIAGNOSISDiagnostic microbiology laboratories and reference laboratories are key for identifying outbreaks of MRSA. Faster techniques for identifying and characterizing MRSA have recently been developed. Normally, the 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 upon 'strong suspicion' and techniques by the treating physician; these include quantitative PCR procedures, which are employed in clinical laboratories for quickly detecting and identifying MRSA strains. 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.

Fluorescent probe before (left) and after (right) addition of S. aureus

Polymer- and colloid-mediated bioassays

Screening Programs

Surface sanitizing

UV SANITIZER

Hand washing

Restriction of Antibiotic use

Proper disposal of hospital gowns

Isolation

Decolonization

TREATMENT

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 (like co-trimoxazole/trimethoprim-sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin (for osteomyelitis), but the drug of choice for treating CA-MRSA is now believed to be vancomycin, according to a Henry Ford

Hospital Study. 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) and daptomycin, are effective against both CA-MRSA and HA-MRSA. The Infectious Disease Society of America recommends vancomycin, linezolid, or clindamycin (if susceptible) for treating patients with MRSA pneumonia. Ceftaroline, a fifth generation cephalosporin, is the first beta-lactam antibiotic approved in the US to treat MRSA infections (skin and soft tissue or community acquired pneumonia only).

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 must be administered intravenously to control systemic infections. Treatment of MRSA infection with vancomycin 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 methicillin-susceptible Staphylococcus aureus (MSSA).

Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new evolutions of the MRSA bacterium have been dubbed Vancomycin intermediate-resistant Staphylococcus aureus (VISA).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.

Studies suggest that allicin, a compound found in garlic, may prove to be effective in the treatment of MRSA.

RESEARCH

ClinicalIt has been reported that maggot therapy to clean out necrotic tissue of MRSA infection has been successful. Studies in diabetic patients reported significantly shorter treatment times than those achieved with standard treatments.Many antibiotics against MRSA are in phase II and phase III clinical trials. e.g.:Phase III : ceftobiprole, Ceftaroline, Dalbavancin, Telavancin, torezolid, iclaprim etc.Phase II : nemonoxacin.Pre-clinicalPhage therapyAn entirely different approach is phage therapy (e.g., at the Eliava Institute in Georgia). Experimental phage therapy tested in mice had a reported efficacy against up to 95% of tested Staphylococcus isolates.[

AntibioticsOn May 18, 2006, a report in Nature identified a new antibiotic, called platensimycin, that had demonstrated successful use against MRSA.A new class of non-β-lactam antibiotics, oxadiazoles, was reported to be effective against MRSA infection in mouse models. The mechanisms of oxadiazoles’ antibacterial effect are the inhibition of the penicillin binding protein, PBP2a and biosynthesis of the bacterial cell wall. It was found to have bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains.

Natural products

A 2010 study noted significant antimicrobial action of Ulmo 90 and manuka UMF 25+ honey against several microorganisms, including MRSA. The investigators noted the superior antimicrobial action of Ulmo 90 honey, and suggested it be investigated further.A separate 2010 study examined the use of medical-grade honey against several antibiotic-resistant strains of bacteria, including MRSA. The study concluded that the antimicrobial action of the honey studied was due to the activity of hydrogen peroxide, methylglyoxal, and a novel compound named bee defensin-1.

Ocean-dwelling living sponges produce compounds that may make MRSA more susceptible to antibiotics.

Some semi-toxic fungi/mushrooms excrete broad spectrum antibiotics, not all of which have been fully identified. The psychedelic mushroom Psilocybe semilanceata has been shown to strongly inhibit the growth of Staphylococcus aureus.An in vitro study showed that the cannabinoids CBD and CBG powerfully inhibit MRSA, in addition to the terpenoid pinene which occurs in cannabis.

Cannabinoids (components of Cannabis sativa), including cannabidiol (CBD), cannabinol (CBN),

(CBC), tetrahydrocannabinol (THC) and cannabigerol (CBG), show activity against a variety of MRSA strains.

Oakin, an Oak extract, has been shown to start killing MRSA immediately and reaches 99.2% at 6 hours, sustaining that kill rate for 48 hours (max time tested).

CONCLUSION

MRSA has effected the lives of millions. This sudden development of resistance of bacteria’s towards antibiotics has become one of the most biggest challenges for the pharmaceutical industry. Everyday we can see that a new antibiotic is developed.The people tend to misuse or take up incomplete doses of drugs and end up developing diseases which require higher dose of drugs to deal with resistance.

In case of MRSA infection the survival rates are 30-50% and even after treatment its not so sure whether the infection will stop. We cannot stop but at least prevent it .

It is very important to maintain proper hygiene and increase awareness about proper usage of drugs and their doses, avoiding half cooked meat,etc.Even if some of these steps are taken we can stop the spread of MRSA.A lot of new techniques have been developed recently hence we can hope to deal with the drug resistance very soon.

“PREVENTION IS BETTER THAN CURE………”

THANKYOU

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ARUNA.MOHAN.DAS