Mechanism of Resistance and Molecular Background of HAMRSA

Resistance to methicillin confers resistance to all beta-lactam antibiotics and requires the presence of the mecA gene, encoding the production of PBP 2a (Chambers 1997). The origin of the mec element is not known. The assembly of the several mec element structures that have been found may have evolved from multiple hosts, possibly among coagulase-negative staphylococci. PBP 2a is a transpeptidase that catalyzes the formation of cross-bridges in bacterial cell wall peptidoglycan, and has a low affinity for all p-lactam antibiotics. It takes over the function of cell wall biosynthesis in the presence of p-lactam antibiotics when normally occurring PBPs are inactivated by ligating p-lactams. The mecA gene is carried on a mobile genetic element known as the staphylococcal cassette chromosome (SCC) mec. Besides the mecA gene itself, the SCCmec element contains regulatory genes, an insertion sequence element, and a unique cassette of recom-binase genes responsible for the integration and excision of SCCmec. At present, five types of SCCmec elements have been identified based on the class of mecA gene complex and the type of ccr gene complex, and are numbered from I to V (Deresinski 2005). Type I SCCmec contains the mecA gene as the sole resistance determinant, whereas SCCmec types II and III contain multiple determinants for resistance to non-p-lactam antibiotics and are responsible for the multidrug resistance commonly found in HA-MRSA isolates. Strains of community-acquired MRSA that have emerged over the past decade have mostly harbored the SCCmec type IV element and they are typically susceptible to multiple antibiotics with non-p-lactam susceptibility patterns resembling those of methicillin-susceptible S. aureus (MSSA) strains prevalent in the community.

Genetic evolutionary analyses have demonstrated that the mecA gene has been transferred into MSSA on at least 20 occasions, having emerged in five phyloge-netically distinct lineages, as well as reemerging within indvidual lineages (Enright et al. 2002). This indicates that the gene for methicillin resistance has been horizontally transferred at least five times in S. aureus. The genetic background represented by CA-MRSA represents the sixth genetic background that is known to contain SCCmec DNA (Deresinski 2005). What is clear from molecular typing studies is that a small number of ecologically successful genetic backgrounds can acquire the methicillin resistance gene and retain a high level of epidemicity. The current understanding is that MRSA arose as a result of the transfer of SCCmec into MSSA. As a point of interest, this phenomenon seems to have occurred infrequently in the past and there are relatively few genotypes of

MRSA as opposed to MSSA, an observation that is backed by a recent study demonstrating that certain S. aureus lineages were more permissive of mecA and its gene product than others (Katayama et al. 2005). These findings suggest that virtually all patients with MRSA infection or colonization have acquired their MRSA strain from an external source, and therefore control efforts must mainly focus on preventing transmission.

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