Methicillin-resistant Staphylococcus aureus (MRSA)

Attack of the Superbug!

by Elizabeth Heller, Kenia Rodriguez, Shirley Shangguan

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Attack of the Superbug! Introduction History Symptoms and Prevalence Genetics Testing Treatment Standard Antibiotic Use: Alternative Treatments: Conclusion References Drafts

 

Introduction

 

    Methicillin-resistant Staphylococcus aureus (MRSA) is a type of infection caused by the bacteria Staphylococcus aureus, better known as ‘staph’. The MRSA strain differs from other strains of staph because the bacteria do not respond to the broad-spectrum antibiotics typically used to treat it ("MRSA Infection", www.mayoclinic.com). These antibiotics include methicillin, penicillin, oxacillin, amoxicillin, and cephalosporins. Staph bacteria can be found on the skin or in the nose of about one-third of the population in the United States. Though most of these individuals have no symptoms, they can still spread the bacteria to others. In otherwise healthy individuals, these bacteria remain harmless unless they enter a cut or wound, at which point they can cause serious infection (“MRSA in Healthcare Settings”, www.cdc.gov).

    MRSA infections are categorized as either Healthcare-associated MRSA (HA-MRSA) or Community-associated MRSA (CA-MRSA).

HA-MRSA is associated with individuals that have been recently been under medical care at hospitals. These individuals are susceptible to the HA-MRSA infections due to their weakened immune systems after surgical procedures or sickness. CA-MRSA is associated with individuals who are considered healthy and do not have compromised immune systems ("MRSA Infecton", http://health.nytimes.com/health/guides/disease/mrsa-infection/overview.html)

 

    Like non-resistant Staph aureus, MRSA is gram-positive, morphologically coccus, and often arranges itself in small clusters. It is a facultative anaerobe and is catalase positive. Unlike other species of Staphylococcus, S. aureus is coagulase-positive (can produce the enzyme ‘coagulase’ which causes clot formation) (Rehm, 2008).

 

History

 

    MRSA first emerged in the UK during the early 1960s (referred to as the 'superbug'), following the introduction of the antibiotic methicillin (Jevons, 1961). Its prevalence remained variable until the 1990s, when a progressive increase of MRSA began around the world. This is illustrated by the increase in proportion of S. aureus strains resistant to methicillin from 2% in 1990 to 40% in 2003 in England and Wales (Johnson et al. 2005). According to data from the CDC, the proportion of infections that are antimicrobial resistant has been growing in the United States as well. In 1974, MRSA infections accounted for only 2% of the total number of staph infections in hospitals; in 1995 it was 22%, and by 2004 it reached an astounding 63% (“MRSA in Healthcare Settings”, www.cdc.gov).

 

Symptoms and Prevalence

 

    MRSA infections have a myriad of symptoms. The most common include infections of the skin and soft tissue. One example is folliculitis, an infection of individual hair follicles that leads to swollen, red areas of the skin and pimples of pus occurring in clusters. Another example is furunculosis, an infection of the skin that causes boils or painful red, pus-filled lumps. Other symptoms include fever, rash, chest pain, fatigue, muscles aches, and headaches. ("MRSA Infecton", http://health.nytimes.com/health/guides/disease/mrsa-infection/overview.html). However, MRSA is also known to cause much more severe effects. One example is necrotizing fasciitis, otherwise known as the flesh-eating bacteria. Necrotizing fasciitis is a life threatening infection characterized by diarrhea, vomiting, inflammation and swelling of the skin and a gradual death of subcutaneous tissue. The death of this tissue causes deep lesions in the skin and eventual septic shock persists (Miller et. Al, 2005). Other potentially fatal infections that can develop include necrotizing pneumonia, an infection of the lungs that results in tissue destruction, and endocarditis, an infection of the inner lining of the heart that causes potentially fatal complications (Rehm, 2008).

    The prevalence of MRSA among hospital acquired S. aureus isolates is below 1% in the Netherlands. However, prevalences in other countries are much higher with Belgium at 28%, France at 33%, Germany at 19%, and the United States at 50% (Wertheim et. al., 2004). Studies concerning CA-MRSA show that the MRSA colonization rate among community members was 1.3%. Community members from whom samples were obtained in health care facilities were more likely to be carrying MRSA than were community members from whom samples were obtained outside of the health care setting. Those studies that excluded individuals with health care contacts found that the MRSA prevalence was 0.2% (Salgado, 2003).

 

Genetics

 

    Penicillin-resistant MRSA has an enzyme called penicillinase that breaks down penicillin. Usually, penicillinase is encoded by a plasmid and can be spread by conjugation or transduction. But unlike penicillin-resistant MRSA, the methicillin-reistant strain is encoded chromosomally (Chambers, 2001; http://www.cdc.gov).

    The resistance mechanism to MRSA starts with acquiring the mecA gene. This gene codes for the penicillin binding protein PBP2A, a protein that has low affinity for β-lactam antibiotics. MecA seems to come from a domestic gene of the susceptible β-lactam gene Staphylococcus sciuri. This gene lives in the skin of domestic and wild animals. Prior to infecting the S. aureus gene, mecA has to be integrated into a molecular vector called the staphylococcal chromosome cassette (SCC). The SCCmec can only be incorporated into a S. aureus cell if one’s genetic background allows for its expression. Only a few of the MRSA strains have been spread globally, and scientists still do not know why S. aureus, which has historically been found in hospital settings, has moved into communities.

    In 1949, shortly after penicillin was introduced to the human population, it was used in veterinary medicine. MecA may have evolved in a penicillinase-free staphylococcus species under the selective pressure of penicillin such as S. sciuri. In this situation, a S. sciuri mecA homologue may have evolved in the skin of domestic animals due to the selecture pressure from using penicillin.

SCCmec may enter the S. aereus cell via transduction by a phage in staphylococcus. Some scientists believe that some S. aureus have protection against “maintaining, transcribing, and translating a plasmid born mecA gene” (de Lencastre). That explains why there are only a few MRSA lineages that have been found in epidemiological studies.

    Community-associated MRSA (CA-MRSA) may have started due to frequent encounters between SCCmec donors (probably methicillin-resistant coagulase negative staphylococci) and MSS recipients that are commonly in individuals within a community. SCCmecIV and SCCmecV have been identified in MRSA clones. In addition, the rise of CA-MRSA could be due to “new high risk human populations and/or lifestyles” (de Lencastre, 2007). This entry of MRSA clones that require a lot of the cell’s resources into hospitals may make drug resistant S. aureus infections harder to treat.

 

Testing

 

    The diagnosis of an MRSA infection is commonly made through screening cultures, using samples of blood, sputum, skin, urine, or drainage from the infected site. However, these methods are often labor intensive and time consuming, requiring at least 48 hours for a negative result and another 1 to 2 days to confirm positive readings. Newer, faster methods include molecular based assays that detect S. aureus-specific sequences and the presence of the mecA gene, which, as discussed above, encodes resistance to methicillin. Unfortunately, the high cost and high operator skill requirement associated with the assays are barriers to its widespread use (Johnson, 2006).

 

Treatment

 

Standard Antibiotic Use:

 

    Both HA-MRSA and CA-MRSA still respond to certain courses of treatment. Vancomycin, rifampicin, tetracycline, clindamycin and trimethoprim are antibiotics currently prescribed to treat the methicillin-resistant strains of S. aureus (Moellering, 2006). However, there is still a risk that these strains will also become resistant to these drugs. In fact, some hospitals are already facing vancomycin-intermediate (VISA) and vancomycin-resistant form of staph (VRSA). In 2002, the first case of true high-level vancomycin-resistant staph was reported in Michigan (Moellering, 2006). Promising new antibiotics are in development, including Linezolid, Daptomycin, and Iclaprim. However, the risk of resistance developing to these antibiotics are still extremely high (Rehm, 2008).

    There are several other downsides to using second and third choice antibiotic treatments. First, they tend to have higher out of pocket costs, and are less effective, so they need to taken for a longer period of time (“MRSA in Healthcare Settings”, www.cdc.gov). Also, some of these treatments are potentially more toxic, which introduces further health risks to the patient. Vancomycin, for example, is both ototoxic (causes kidney damage) and nephrotoxic (causes liver damage) (Moellering, 2006). Beyond personal costs, second choice treatments can also be expensive for society as a whole; they mean heavier usage of the health care system and prolonged hospital stays. The costs of developing these alternative treatments can be burdensome as well (“MRSA in Healthcare Settings”, www.cdc.gov).

 

Alternative Treatments:

 

    Several innovative treatments are under investigation. Once such treatment is maggot therapy (yes, those same pesky critters that appear in rancid meat and rotting corpses). Maggots can be used to remove dead, damaged, or infected tissue by secreting proteolytic enzymes, which break down it down into a sort of soup that the maggots then ingest. This improves the healing potential for the surrounding healthy tissue. How maggots attack the infection itself is less well known; along with the digestion and subsequent lysing of the bacteria by the maggot, it has been posited that the ammonia (which would raise pH) or other agents in their secretion have an antimicrobial effect. However, only specific species of maggot can be used medically, as some maggots will attack healthy tissue as well (Bonn, 2000).

 

    A study by Rashel et al. showed that cloned (purified) phage lysin was successful in protecting mice against MRSA and VRSA infection. Lysin, a bacterial peptidoglycan-degrading enzyme used by bacteriophages to infect the cell for replication, was taken from the staph aureus-specific bacteriophage MR11. The degradation of the bacteria’s cell wall causes it to lyse, thereby killing the infectious cells and preventing the bacteria from spreading further. The lysin can be administered topically and through injection. Because of the high specificity of the lysine, other indigenous bacterial flora are unlikely to be affected by the treatment. Also, mutations that result in resistance to phage lysin are very rare (Rashel et. al, 2008).

 

    Another promising treatment still being developed involves the use of nanoparticles to deliver antibiotics directly to MRSA-infected sites (Turos et. al, 2007). In Turos’ study, penicillin-bound polyacrylate nanoparticles (a synthetic product resulting when the antibiotic is fused with a polymer via covalent conjugation) were tested in vitro against both Methicillin-susceptible (MSSA) and Methicillin resistant staph. Though its antibiotic activity is not as strong as that of penicillin alone against MSSA, it was used successfully against both MSSA and MRSA. The results of the study indicate that the nanoparticle protects the antibiotic from degradation by the beta-lactamase produced by resistant bacteria, thereby restoring its efficacy (Turos et. al, 2007)

 

Conclusion

 

    MRSA first emerged in healthcare environments and has since evolved into community associated form through various mechanisms of resistance acquisition. While infection has many unpleasant superficial symptoms it is also implicated in deeper, more life threatening conditions. While alternative antibiotics can be used against the bacteria, the risk of MRSA developing resistance to these alternative forms is high. Innovative alternative treatments are currently in development. However, maintaining basic personal hygiene is the best method to avoid infection.

 

 

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References

 

Bonn, D. Maggot therapy: an alternative for wound infection. The Lancet. 2000. 356(9236): 1174.

 

Center for Disease Control. “MRSA in Healthcare Settings”. Released: October 3, 2007. Accessed: May 6th, 2008.

http://www.cdc.gov/ncidod/dhqp/ar_MRSA_spotlight_2006.html

 

Chambers, H.F. The Changing Epidemiology of Staphylococcus aureus?. Emerging Infectious Diseases (CDC). 2001. 7(2)

http://www.cdc.gov/ncidod/eid/vol7no2/chambers.htm

 

de Lencastre, H., Oliveira, D., & Tomasz, A. (2007). Antibiotic resistant staphylococcus aureus: A paradigm of adaptive power. Current Opinion in Microbiology, 10(5), 428-435.

 

Johnson, G., Millar, M.R., Matthews, S., Skyrme, M.,Marsh, P., Barringer, E., O'Hara, S., and Wilks, M. Evaluation of BacLite Rapid MRSA, a rapid culture based screening test for the detection of ciprofloxacin and methicillin resistant S. aureus (MRSA) from screening swabs. BMC Microbiology. 2006. 6: 83.

 

Miller, L.G., Perdreau-Remington F., Rieg G., Mehdi S, et al. Necrotizing Fasciitis Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus in Los Angeles. The New England Journal of Medicine. 2005. 352(14): 1445-1454.

Rehm SJ. Staphylococcus aureus: The new adventures of a legendary pathogen. Cleveland Clinic Journal of Medicine. 2008. 75(3):177-192.

 

Moellering, R.C. The Growing Menace of Community-Acquired Methicillin-Resistant Staphylococcus aureus. Annals of Internal Medicine. 2006. 144(5): 368-370.

 

Mayo Clinic. MRSA Infection. Published: Nov 9, 2007. Accessed: May 6th, 2008.

http://www.mayoclinic.com/health/mrsa/DS00735/DSECTION=1

MRSA Infection. The New York Times. Reviewed: January 25, 2008. Date accessed: May 6, 2008.

 

Rashel, M., Uchiyama, J., Ujihara, T., Uehara, Y., Kuramoto, S., Sugihara, S., Yagyu, K., Muraoka, A., Sugai, M., Hiramatsu, K., Honke, K., Matsuzaki, S. Efficient Elimination of Multidrug-Resistant Staphylococcus aureus by Cloned Lysin Derived from Bacteriophage MR11. The Journal of Infectious Diseases. 2007. 196: 1237–1247.

 

Salgado, C.D. Community‐Acquired Methicillin‐Resistant Staphylococcus aureus: A Meta‐Analysis of Prevalence and Risk Factors. Clinical Infectious Diseases. 2003. 36(2):31.

 

Turos, E., Reddy, G.S.K., Greenhalgh, K., Ramaraju, P., Abeylath, S., Jang, S., Dickey, S., Lim, D.V. Penicillin-bound polyacrylate nanoparticles: Restoring the activity of b-lactam antibiotics against MRSA . Bioorganic & Medicinal Chemistry Letters 2007. 17: 3468–3472.

 

Wertheim H.F.L., Vos M.C., Boelens H.A.M., Voss A., Vandenbroucke-Grauls C.M.J.E., Meester M.H.M, Kluytmans J.A.J.W., van Keulen P.H.J, Verbrugh H.A. Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission in the Netherlands: the value of search and destroy and restrictive antibiotic use. Journal of Hospital Infection. 2004. 56(4):321-325.

 

 

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