'Pathogen extraordinaire': Methicillin-resistant Staphylococcus aureus (MRSA)
The Center of disease control (CDC) gives the following summary about MRSA: “Methicillin-resistant Staphylococcus aureus (MRSA) causes a range of illnesses, from skin and wound infections to pneumonia and bloodstream infections that can cause sepsis and death. Staph bacteria, including MRSA, are one of the most common causes of healthcare-associated infections. “ A paper describing some of the toxins Stahylococcus produces calls it a ‘pathogen extraordinaire” and “one of the more formidable disease-causing bacteria”. Nevertheless, the CDC now lists three other organisms as the most urgent threats. MRSA is among the most ‘serious’ threats, and is still regarded a dangerous enemy, but statistics show that healthcare associated severe infections have declined by about 50% between 2005 and 2011, perhaps because of heightened awareness and better safety practices.
During the same time, the community associated infections did not decrease. However, there are new, effective antibiotics for treating skin infections, with more being developed - http://www.the-scientist.com/?articles.view/articleNo/40156/title/New-Antibiotics-to-Combat-Resistant-Bugs/ and new research is being conducted on antibiotic resistance, for example to use bacterial viruses specialized for the destruction of antibiotic resistance genes.
Staphylococcus aureus (SA), the organism
A round ‘coccal’ organism, it forms grape-like bunches, and is golden colored, as its name implies. Many healthy people carry SA on their skin or nasal cavities. But the organism is notorious for spreading further into the tissues, creating deep trouble.
Staphylococcus aureus, cultured on an agar plate for drug sensitivity test
Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin is an antibiotic that was originally developed and manufactured to treat penicillin-resistant organisms. It works similarly to penicillin, i.e. by binding and inhibiting an enzyme (sometimes called penicillin binding protein PBP) that takes part in the synthesis of bacterial cell wall. Thus, methicillin belongs to the family of beta-lactam antibiotics, like penicillin. The reason it worked successfully to treat penicillin-resistant organisms was that it did not bind to the enzyme penicillinase that inactivates penicillin, and therefore avoided being broken down. Resistance to methicillin arose not by organisms becoming able to break it down more efficiently, but by acquiring a second PBP2 (penicillin binding protein 2) that had low affinity to methicillin and other similar beta-lactam antibiotics. This allowed organisms that had this protein to carry on synthesizing cell wall components in the presence of methicillin and similar compounds.
Methicillin has since been replaced by similar antibiotics, but with more advantageous properties; however, the name survives in describing the condition of resistance.
The Staphylococcal chromosomal cassette (SSC, often referred to as Staphylococcal cassette chromosome) that determines resistance against methicillin
If resistance to methicillin and similar antibiotics is dependent on PBP2, how was this protein acquired by S. aureus? The gene is located in a ‘mobile island’ on the bacterial chromosome. The gene encoding the PBP2 protein is a small part of the long, complicated island that also contains regulatory elements for the synthesis of resistance factors against other antibiotics, such as tetracycline, aminoglycosides such as kanamycin, and many other groups. There are also genes in the SCC responsible for the integration and excision of the cassette. People are not sure about the source of the first island that inserted into S. aureus – which happened only 2 years after the introduction of methicillin! In fact it is believed the acquisition of the mobile island happened several times during the evolution of MRSA.
To understand the spreading of the cassette and of the organism, and to determine how the organism’s genetic background influenced the structure of the cassette, several methods have been developed for the characterization of the bacterial chromosome, and of the cassette itself. Seven types of the cassette have been distinguished.
Types I, IV, V, VI and VII are relatively short islands, carrying resistance only for beta-lactam type (i.e. methicillin) antibiotics. Type II and III are much longer, owing to the insertion of plasmids and other mobile elements ferrying further resistance genes into the SCC and making the organisms that hold them resistant to multiple antibiotics (‘multiresistant’). It turns out that most hospital acquired infections are caused by MRSA isolates carrying the long form of the cassette, while community acquired organisms contain the shorter form.
"My leg. The top red thing is a methicillin-resistant staph infection"
Hospital Associated (HA-MRSA) and Community Associated (CA-MRSA) infections
The first emerging MRSA isolates were all associated with hospital stay. As may be expected, since the pathogenic strains contain the long, multiresistant cassettes (SCCs), these are resistant to many antibiotics. Community acquired infections appeared later, in the late 1990s and contain the shorter cassettes. By today, with CA-MRSA dispersing into hospitals and vice versa, the distinction between these terms is starting to fade. Although community acquired infections by CA-MRSA are not multiresistant, they are often described as more virulent (extremely damaging). This seems counterintuitive. However, antibiotic resistance is not the only weapon Staphylococcus can deploy.
The CA-MRSA is associated with a cytotoxin, called the Panton-Valentine leukocidin (PVL), which bores holes into cell membranes and lyses cells. It was considered the main cause of CA-MRSA being such an efficient pathogen, but there is some recent experimental evidence to the contrary. Thus, other toxic molecules may be responsible for the virulence of CA-MRSA. And Staphylococcus has plenty of toxic molecules!
The arsenal of Staphylococcus
This is the expression that came to mind upon reviewing the molecules Staphylococcus uses to convert tissues of the host into nutrients, to disable its defenses, and in general, to promote its own successful dissemination. They belong into the following groups:
Enzymes: hyaluronidase, which breaks the extracellular matrix down; coagulase, which clots blood; staphylokinase, which breaks down fibrin, and many other enzymes that break down the internal components of cells, all help to provide nutrients for Staph or to spread the organism.
---Staphylococcal enterotoxins cause food poisoning.
---The toxic shock syndrome protein can, in very low concentrations, induce the immune system to overexpress inflammatory molecules, which can result in fever and possibly fatal shock.
---Exfoliative toxins cause the staphylococcal scalded skin syndrome.
---The Panton-Valentine leukocidin mentioned above
Other virulence factors (molecules that contribute to pathogenicity) include Staphylococcal protein A. The role of this protein is to bind immunoglobulin molecules in a conformation that prevents the destruction of the bacterium by the immune system. The golden pigment that provides the name for the organism is also a protective agent.
Cutaneous abscess caused by methicillin-resistant Staphylococcus aureus
Treatment and Prevention
Hospital Associated MRSA (HA-MRSA)
Although according to several sources the incidence of HA-MRSA blood stream infections is declining, it still is a formidable problem. Treatment is with other antibiotics belonging to different classes such as vancomycin, linezolid etc, some of which have to administered intravenously. Unfortunately, HA-MRSA may become resistant these antibiotics as well. A few years ago a promising new antibiotic, platensimycin, was described, but at present clinical trials with it are not yet adequate. The same is probably for other ‘newbies’. But, according to ‘Healthline’ (http://www.healthline.com/health-news/new-mrsa-drug-approved-081214#1) the FDA has approved a new intravenous antibiotic (Oritavancin ) for treatment of MRSA.
As with many, or all, diseases, prevention is crucial in combating them. The CDC guideleines are given at http://www.cdc.gov/mrsa/healthcare/clinicians/precautions.html, and include hand hygiene, gloving, etc as well as directions for patient isolation. Whereas these guidelines are mainly for healthcare providers, it makes sense to follow good handwashing, avoiding contact and similar precautions when visiting patients suspected or identified as harboring MRSA. Read the guide, or ask hospital personnel about precautions if you are visiting a hospital.
Community Associated (CA-MRSA)
In the community MRSA often causes skin infections. Prevention is, again, the best defense. Any skin infection that is painful and swollen may be suspected to be caused by MRSA, see the site of the CDC (http://www.cdc.gov/mrsa/community/index.html). Never pop a sore, cover it with clean bandage and see a doctor. Handling small wounds yourself – if they show signs of infection – may spread the bacterium further, so that it may penetrate small abrasions and cause further trouble. Also, always keep good personal hygiene habits: do not share face cloths, cover wounds, and practice thorough hand washing with soap.