Hospital-acquired Methicillin Resistant Staphylococcus Aureus (MRSA)
By: Anthony Alexander
Introduction
Staphylococcus aureus is a spherical microbe and a member of the bacteria domain. This bacterium can be found naturally on the skin and in the mucus membranes of humans most importantly. In fact, Staphylococcus aureus can be found in the nostrils of up to 30% of people (1). The bacteria is spread most commonly through human contact be it hand-to-hand, from a wound secretion or mucus.
The spherical bacteria is gram-positive (contains a peptidoglycan layer in its cell wall) and forms colonies that grow in two planes (2). Staphylococcus aureus however lacks flagella and as a result is non-motile. The genome of Staphylococcus aureus was first sequenced and mapped by Peter A. Pattee for the strain NCTC 8325 (2). This strain had a circular genome containing approximately 2,900 open reading frames, 61 tRNA genes, 3 structural RNAs and 5 complete ribosomal RNA operons (2). The aspect of Staphylococcus aureus and its genome that is most concerning revolves around the plasmids that are incorporated/associated with this bacterium’s genome. The plasmids that this bacterium contains often code some type of antibiotic resistance. Over time, Staphylococcus aureus was able to acquire antibiotic resistance through conjugation (horizontal gene transfer) of a plasmid containing a transposon, Tn 1546 (2). The transposon Tn 1546 contains the gene mecA which encodes a modified penicillin-binding protein granting Staphylococcus aureus methicillin, and more broadly, penicillin resistance.
Methicillin is a beta-lactam antibiotic similar to penicillin. Beta-lactam antibiotics target penicillin-binding proteins. Once bound to the protein, the antibiotic prevents proper peptidoglycan and cell wall formation so that cells will eventually burst as the bacteria attempt to grow larger (3). Penicillin and similar beta-lactam ring antibiotic resistance can be achieved in two main ways; first bacteria can acquire a gene (through horizontal gene transfer) encoding beta-lactamase enzyme which cleaves the critical ring structure of this particular type of antibiotics preventing them from binding the penicillin-binding proteins and disrupting cell wall formation. Second, some bacteria can produce a modified penicillin-binding protein that no longer actually binds the antibiotic which again prevents the desired effects of the antibiotic (3). Methicillin is frequently used to fight bacteria that produce beta-lactamase but is still susceptible to the second form of bacterial resistance to beta-lactam antibiotics. Bacteria like methicillin resistant Staphylococcus aureus are currently of special interest, especially in hospitals, because very few drugs (antibiotics) are still effective against them.
Antibiotic Resistance in Staphylococcus aureus in Greater Detail
High replication rates coupled with the great ability of to perform horizontal gene transfer (especially through conjugation) allow bacteria to develop antibiotic resistance and to spread it quickly. By 1942, the first penicillin resistant strains of Staphylococcus aureus had been isolated in hospitals (4). Theses penicillin resistant strands contained a plasmid encoding a penicillin-hydrolyzing enzyme, penicillinase. Less than 20 years after the first strains of Staphylococcus aureus were found to be resistant to penicillin, 80% of all strains had acquired penicillin resistance. As new antibiotics such as methicillin and vancomycin were used to fight Staphylococcus aureus, resistance to these antibiotics also began to develop. Methicillin was first used to treat Staphylococcus aureus in 1959 and just after 2 years of use, methiccillin-resistant Staphylococcus aureus (MRSA) strains had be isolated (4). Methicillin resistance first developed and became transferable in the mecA gene. The mecA gene encodes a protein, penicillin-binding protein PBP2a, which cannot be bound by Beta-lactam antibiotics (penicillin, methicillin…) and in turn prevents the disruption of cell wall formation by these antibiotics. This gene is located on mobile genetic element called the Staphylococcal Cassette Chromosome mec (SCCmec)(4).
Five types (Types I-V) of SCCmec have been isolated and characterized. They vary in size from 20.9 to 66.9 kb. The five SCCmec types were isolated sequentially as one would expect, but they were each isolated initially in different regions across the globe. SCCmec Type I was isolated in 1961 in the UK, Type II in 1982 in Japan, Type III in 1985 in New Zealand and finally Type V at the start of the 21st century in Australia (4). Not only might one find it surprising that the different types of SCCmec would have been isolated in areas so far apart from each other, but it is also interesting that not all of the different SCCmecs encode/provide the same resistance. Types I, IV and V only encode resistance to beta-lactam antibiotics where as Types II and III encode additional drug resistance genes. The additional drug resistance genes include the transposon Tn554 which codes for an ermA gene providing inducible resistance to macrolide, lincosamide and streptogramin(4). So how did the first MRSA isolates lead to the development of the MRSA isolates found today?
In a paper by Deurenberg et al. two theories establishing the relationship between the first MRSA strains and present day MRSA strains are proposed. The first is called the single-clone theory which states that all MRSA clones or present day strains have a common ancestor. This first theory also states that SCCmec was introduced only once into Staphylococcus aureus. After its “introduction” or formation, SCCmec developed into types I-V through mutations overtime. The second theory is called the multi-clone theory. This second theory suggests that SCCmec was introduced several times into different Staphylococcus aureus. According to the paper by Deurenberg et al. the multi-clone theory has received greater support recently. It appears as though the different SCCmec tpes have been acquired by Staphylococcus aureus strains with different genetic backgrounds. This is also a likely reason as to why the different types were first isolated in regions so far apart from each other.
Prevalence, Type and Spread of MRSA
As described previously, once an antibiotic resistance is developed, it can be transferred and spread through bacteria strains very rapidly. In England and Wales, less than 2% of Staphylococcus aureus strains were methicillin-resistant in 1990 but by 2002 42% of Staphylococcus aureus strains were methicillin-resistant (5). In a paper by Carnicer-Pont et al. it is stated that an estimated 300,000 cases of hospital-acquired MRSA occur each year in England leading to 5,000 deaths. The main focus of the paper by Carnicer-Pont et al. is achieving a better understanding of how MRSA is spread within hospitals. From the study, it was determined for the hospital in which the study took place that MRSA strains were most frequently acquired as a result of surgical procedures. The insertion of urinary catheters and central lines accounted for 51% and 39% of the MRSA acquired cases respectively. Surgical site infection accounted for the lowest percent of the cases (16%) but time at risk accounted for 36% of the cases. In the study time at risk was considered to be a period of being exposed to or in condition allowing the spread of MRSA for a period greater than 7 days. If not appropriately accounted for, MRSA strains can spread easily and quickly in a hospital setting.
The spread of MRSA within hospitals is not the only concern however. In a study done throughout 4 of 34 German university hospitals by Chaberny et al. the type of MRSA infections were studied. The majority of MRSA infections were wound infections (56.9%) with pneumonia cases being the second most common (21.0%). Potentially the most dangerous infection type, bloodstream infections accounted for 15.1% of the cases and urinary track infection accounted for 6.9%. One of the most important pieces of information provided by this study was the fact that of all the infected MRSA patients, 51.5% had already been infected at their time of admission. This suggests that not only should the spread of MRSA infections to non-infected patients in hospitals be a major concern, but that the introduction of new MRSA strains to hospitals by patients infected prior to admission should be a concern as well. So how can hospitals deal with the introduction of new MRSA strains and the spread of MRSA within their buildings? Some of the best ways to prevent the spread of MRSA is through screening and resulting isolation.
