Community-acquired methicillin-resistant Staphylococcus aureus: community transmission, pathogenesis, and drug resistance

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is able to persist not only in hospitals (with a high level of antimicrobial agent use) but also in the community (with a low level of antimicrobial agent use). The former is called hospital-acquired MRSA (HA-MRSA) and the latter community-acquired MRSA (CA-MRSA). It is believed MRSA clones are generated from S. aureus through insertion of the staphylococcal cassette chromosome mec (SCCmec), and outbreaks occur as they spread. Several worldwide and regional clones have been identified, and their epidemiological, clinical, and genetic characteristics have been described. CA-MRSA is likely able to survive in the community because of suitable SCCmec types (type IV or V), a clone-specific colonization/infection nature, toxin profiles (including Pantone-Valentine leucocidin, PVL), and narrow drug resistance patterns. CA-MRSA infections are generally seen in healthy children or young athletes, with unexpected cases of diseases, and also in elderly inpatients, occasionally surprising clinicians used to HA-MRSA infections. CA-MRSA spreads within families and close-contact groups or even through public transport, demonstrating transmission cores. Re-infection (including multifocal infection) frequently occurs, if the cores are not sought out and properly eradicated. Recently, attention has been given to CA-MRSA (USA300), which originated in the US, and is growing as HA-MRSA and also as a worldwide clone. CA-MRSA infection in influenza season has increasingly been noted as well. MRSA is also found in farm and companion animals, and has occasionally transferred to humans. As such, the epidemiological, clinical, and genetic behavior of CA-MRSA, a growing threat, is focused on in this study.

Fig. 1

eBURST analysis of S. aureus. Data from the MLST website (http://www.mlst.net/) and eBURST software (http://eburst.mlst.net/), 23 December 2009. Major CC and ST types are indicated

Fig. 2

Worldwide distribution of major HA-MRSA clones. Data from Ref. [, , –57]. The colored areas indicate the areas of each spreading clone. Yellow represents the region where the archaic clone was isolated. Orange represents the region where the Iberian clone was isolated. Pink represents the region where the New York/Japan clone was isolated. Lime green represents the region where the EMRSA-16 clone was isolated. Blue represents the region where the ST239 clone, including the Hungarian clone, Brazilian clone, and Russian clone, was isolated. Purple represents the region where the Berlin clone was isolated. Green represents the region where EMRSA-15 was isolated. Gray represents the region where the pediatric clone was isolated. Graphs indicate the rate of MRSA in all S. aureus isolates from the hospitals in each country

Fig. 3

Diseases related to CA-MRSA infection. Data from Refs. [, , , –, –95]. Arrow in computer-assisted tomography image points to pelvic abscess. Numbers in parentheses represent incidence of the disease

Fig. 4

Scanning electron micrograph showing ST22 MRSA and its biofilm (a) and family pedigree with ST22 MRSA infection (b). Data are from Ref. [144]. a Strains were grown on trypticase soy agarII with 5% sheep blood at 37°C overnight. Bar is 1 μm. b Square and circle represent male and female, respectively. Closed mark represents the person who was colonized on infected with MRSA

Fig. 5

Distribution of MRSA and MRCNS in the body. Data from Refs. [144, 155]. Percentages show MRSA incidence isolated from patients and family members or MRCNS incidence isolated from healthy volunteers

Fig. 6

Structures and functions of PVL. a Data from Refs. [, –204]. Protein Data Base (PDB) codes of PVL-F monomer (PDB code, 1PVL) [196] and PVL-S monomer (PDB code, 1T5R) [197] were downloaded from the RCSB Protein Data Bank (http://www.pdb.org/) [198], and their crystal structures were reconstructed using SWISS-MODEL and the Swiss-Pdb Viewer (http://www.expasy.org/spdbv/) [199]. b Schematic representation of primary structures of recombinant histidine (His)-tagged PVL-S (H-PVL-S) and PVL-F (PVL-F-H) and their cell lysis activities are shown. Necrosis of human PMNs and monocytes was determined by morphological change and trypan blue staining. Percents of cell lysis (mean ± SD) are shown (black lines, human PMNs; blue line, human monocytes). In the boxes, light micrographs of PMNs (incubated with the indicated concentrations of PVL) are also shown. c PVL-induced apoptosis of human PMNs was detected by TUNEL staining (green) under a fluorescent microscope. Nuclei were also stained with propidium iodide (PI). d Neutralization of PVL activity with intravaneous immunoglobulin G (IVIG) was examined. PVL proteins were pre-incubated with the different concentrations of IVIG for 15 min at 37°C and then incubated with human PMNs

Fig. 7

Schematic representation of the mutation sites in the PVL genes (a), phyrogenetic analysis of the PVL genes (b), and amino acid substitution sites in three-dimensional structures of PVL-S and PVL-F proteins (c). Data, in part, from Refs. [32, 200, 201]. a A schematic representation of the PVL gene core sequence of ST30 CA-MRSA (GenBank, AB186917) is shown. S and Mature represent the sequences encoding signal peptides and mature proteins, respectively. The sites of nucleotide substitutions and amino acid substitutions are indicated below the scheme. b A phylogenetic tree of the PVL gene is shown. Box colors correspond to those of amino acid substitutions in a. Clones indicated as the same color carry PVL genes giving the same amino acid sequence. The PVL gene core sequence [including MRSA ST30 (its single locus variant ST1335) and MSSA ST50] is indicated as a black-lined red box. c Positions of amino acid substitutions (shown in a) are indicated in three-dimensional structures of (PDB code, 1PVL) [196] and PVL-S (PDB code, 1T5R) [197]. PDB codes were downloaded from the RCSB Protein Data Bank (http://www.pdb.org/) [198], and crystal structures were reconstructed using SWISS-MODEL and the Swiss-Pdb Viewer (http://www.expasy.org/spdbv/) [199]. For the crystal structures, β-sandwich domain is yellow in PVL-S and light yellow in PVL-F, rim domain is blue in PVL-S and light blue in PVL-F, and pre-stem domain is green in PVL-S and dark green in PVL-F. Deduced mode of action of PVL was constructed according to the Refs. [, , –204]. Amino acid substitutions in PVL-S may alter the spectrum of its receptor recognition

Fig. 8

Structures of the USA300 genome (a) and ACME-SCCmecIVa linkage structure (b). Data from Ref. [72]. a Genomic structures of the USA300 chromosome (accession no. NC 007793) and plasmids (accession nos. NC 007790, NC 007791, and NC 007792) are shown. Positions of the ACME-SCCmecIVa linkage, spa, coagulase gene (coa), seven housekeeping genes for MLST, drug resistance genes, and virulence genes including SaPI structures are also indicated. b The ACME-SCCmecIVa linkage structure (orfX–orfY region [137]) is shown. Positions of the mec complex, ccr complex (in SCCmecIVa), acr cluster, opp-3 cluster (in ACME), orfX, and orfY are indicated. Sequences at the 5′- and 3′- ends of SCCmecIVa and ACME are also shown below the scheme. The positions of direct and inverted repeats are indicated by green arrows

Fig. 9

Basic structures of SCCmec. Data from Refs. [–28, 32, 137]. Roman numerals in parentheses represent a new type of SCCmec proposed by the SCCmec Working Committee (IWG-SCC). Arrows indicate the region of detection by PCR method to decide the SCCmec type. ACME is located downstream of SCCmecIVa in USA300

Fig. 10

SCCmec structures containing the ccrC-carrying unit. Data of SCCmecVII (current from SCCmecV) from Ref. [137]. The structure of the ccrC-carrying unit of SCCmecVII [137] is indicated below. The position of the ccrC-carrying unit in each SCCmec structure is indicated as gray

Fig. 11

Chemical structures of aminoglycosides and target residues of enzymatic modification. Chemical structures of gentamicin, kanamycin, and arbekacin are shown. Hydroxyl and amino residues shown in red and blue, respectively, are the targets of the enzymes. The inactivating enzymes are from Table 2

Fig. 12

Model for translational regulation of ermC expression (a) and D test (b, c). Data from Refs. [298, 299]. a Secondary structures upstream of ermC mRNA in the absence and presence of erythromycin are shown. The leader peptide sequence (19 amino acids) and ermC are indicated as gray and dark gray lines, respectively. SD-1 Shine-Dalgarno sequence for leader peptide translation, SD-2 Shine-Dalgarno sequence for ermC translation. In the absence of EM, SD-2 is masked by stem-loop (constructed by sequences 3 and 4). In the presence of EM, a complex of ribosome and EM tightly binds to the leader peptide sequence. This induces disruption of the two stem-loops, resulting in initiation of ermC translation from unmasked SD-2. b, c Results of D test of ermC-positive strain (b) and ermC-negative erythromycin-resistant strain (c) are shown. EM erythromycin, CLDM clindamycin