Frequent emergence and limited geographic dispersal of methicillin-resistant Staphylococcus aureus

Abstract

A small number of clonal lineages dominates the global population structure of methicillin-resistant Staphylococcus aureus (MRSA), resulting in the concept that MRSA has emerged on a few occasions after penicillinase-stable beta-lactam antibiotics were introduced to clinical practice, followed by intercontinental spread of individual clones. We investigated the evolutionary history of an MRSA clone (ST5) by mutation discovery at 108 loci (46 kb) within a global collection of 135 isolates. The SNPs that were ascertained define a radial phylogenetic structure within ST5 consisting of at least 5 chains of mutational steps that define geographically associated clades. These clades are not concordant with previously described groupings based on staphylococcal protein A gene (spa) typing. By mapping the number of independent imports of the staphylococcal cassette chromosome methicillin-resistance island, we also show that import has occurred on at least 23 occasions within this single sequence type and that the progeny of such recombinant strains usually are distributed locally rather than globally. These results provide strong evidence that geographical spread of MRSA over long distances and across cultural borders is a rare event compared with the frequency with which the staphylococcal cassette chromosome island has been imported.

Fig. 1.

Minimum spanning tree based on 156 BiPs discovered in 46,483 bps of DNA from each of 135 S. aureus ST5 isolates from a global collection. Circle size is proportional to haplotype frequency, and line length is proportional to the number of mutational steps between haplotypes. (A) Colors indicate the countries of origin of the isolates. Fourteen lineages that consist of at least 2 haplotypes are labeled “A” through “N.” Numbers of some haplotypes referred to in the text are indicated. (B) Colors indicate the type of SCCmec in each of the MRSA isolates. SCCmec elements that are non-typeable on the basis of current PCR schemes probably represent SCCmec variants, because they displayed recombinase gene (ccrB) sequences that were < 93% homologous to published ccrB sequences. Roman numerals indicate events of SCCmec acquisition that explain the observed distribution of SCCmec elements in the most parsimonious way. The actual number of SCCmec acquisitions may be higher. (C) Colors indicate homoplasies among spa sequences. The emergence of spa sequences that already exist elsewhere in the tree is labeled with text. This tree provides a parsimonious explanation for the homoplasies, but alternative scenarios exist that invoke the same or larger numbers of homoplasies for the observed distribution of spa sequences. For example, the interpretation shown here invokes the repeated evolution of t002 through the acquisition of 3 contiguous sequence repeats, whereas an alternative explanation is that t045 evolved through the loss of those 3 repeats.

Fig. 2.

Geographic distribution of phylogenetic lineages “A” through “N” from Fig. 1A. Colors indicate the phylogenetic affiliations of 135 isolates.