**7. Conclusions**

widespread [230]. In addition, only three SCC*mec* types (IV, V, VI) have been discovered from horses [218]. Interestingly, no MRSA was isolated from 300 horses on 14 farms in Slovenia, 497 horses on 50 farms in Canada, 87 horses in Austria, and 200 horses in the Netherlands [231–233]. ST22 and ST1117 isolates from horses in Germany had IEC genes, such as *chp, sak*, and *scn* [183]. On the other hand, ST8, ST254, and ST398 strains did not carry those genes.

An analysis of MRSA and MSSA from animals and humans spanning 19 countries and four continents indicated that the CC398 lineage originated in humans as MSSA [167]. After its transmission to livestock, CC398 became resistant to tetracycline, probably because of the heavy tetracycline use in pig production [22]. However, many tetracycline-resistant MRSA strains are found in horses despite the fact that tetracycline is either not used much [229] or sparingly used [93, 229]. Among bovine MRSA isolates tested, most of them were resistant to β-lactam antibiotics [34] as well as tetracycline, erythromycin and gentamicin. CC398 has also been reported to be highly resistant to several other antibiotics, such as ciprofloxacin, tobramycin, clindamycin, and trimethoprim-sulfamethoxazole [234]. Antimicrobial resistance patterns of MRSA and MSSA isolates in Hong Kong were very similar [81]. The only MRSA CC398 isolate that has exhibited resistance against daptomycin and intermediate susceptibility to vancomycin has been described in a case-report from an Italian hospital [235]. Two other isolates, one from a ventilator-associated pneumonia of a farmer and one additional porcine isolate, were also described as resistant to linezolid and possessed the *cfr* gene which is located on transferable plasmids [235]. An outbreak with HA-MRSA ST125 containing *cfr*, reported from a Madrid hospital in 2010 [236], was followed by reports on the emergence of nosocomial coagulase negative staphylococci containing *cfr* [40]. This gene was previously found in staphylococci from animals in Europe [237, 238] but has also been reported in humans in Colombia and the USA [239, 240]. Distribution of the *cfr* gene in MRSA isolates is alarming because, besides linezolid, it confers resistance to oxazolidinones, phenicols, lincosamides, streptogramin A, and pleuromutilins, including the topical antibiotic retapamulin that is used

About 50% of LA-MRSA CC398 isolates, besides being resistant to antimicrobial agents, also exhibit resistance to copper and zinc mediated by the *czrC* gene [130, 243]. The use of zinc as feed additives may have favored spread of the *czrC* gene in LA-MRSA [130]. So far, this gene has only been found in LA-MRSA [130, 243] but an extended use of copper coating of biomaterials in orthopedic surgery and traumatology, as well as copper surfaces in hospitals, might select for *czrC*-positive HA-MRSA as well. The trimethoprim-resistance gene *dfrK*, located close to *tetL* in LA-MRSA ST398, has also been found on a plasmid [244]. The *tetL* gene was identified in MRSA isolated from diverse livestock animals and meats from different regions of the world [97, 245, 246]. Kadlec and Schwarz demonstrated the presence of plasmid pKKS25-associated resistance genes, *ermT, dfrK*, and *tetL*, in MRSA obtained from a nasal swab of a young sow in Germany [247]. A porcine MRSA ST398 was shown to contain a transposon Tn*6133* carrying *ant(9)-Ia* and *ermA* genes and a plasmid pKKS825 [248, 249] harboring the resistance genes *vgaC* and *vgaE, aadD, tetL*, and *dfrK* [248–250]. In Germany, the *vgaE* gene was detected in MRSA ST398 isolated from cattle, turkeys, and chicken and turkey meats

**6.3. Antibiotic resistance and enterotoxin genes in LA-MRSA CC398**

76 Frontiers in Frontiers in Staphylococcus Aureus *Staphylococcus aureus*

for treatment of human skin infections [239, 241, 242].

MRSA contamination in food-producing and companion animals poses a serious threat to public health. Incidences of identical LA-MRSA strains in pig farms and persons in close contact with food producing and companion animals suggest a clear link for transmission of these strains between humans and animals. While MRSA isolates from companion and foodproducing animals are known to infect humans, the reverse is also true. Studies reviewed in this report indicate an initial transfer of MSSA from humans to animals by deletion of immunomodulatory genes and prophage ØSa3, necessary for human infection but not required for infection in animals, and acquisition of tetracycline and methicillin resistance genes (**Figure 2**). The MRSA that evolved in animals started showing up in humans that were in close contact with them and exhibited traits specifically found in animal isolates, indicating a reverse transmission from animals to humans. Initial reports of MRSA in animals did not indicate the presence of host adaptation, enterotoxin, virulence, and antimicrobial resistance genes in them but they are becoming more prevalent and it is feared that these animals could serve as a reservoir for such strains and play an important role in zoonotic transfers.

Documentation of MRSA isolates (ST59-t437–V) from cattle containing the *pvl* gene and other virulence factors, such as *chp, scn, seb, sek*, and *seq*, toxic shock syndrome toxin 1 (*tsst1* or *tst*) gene and hemolysin, protease, superantigen-like protein, capsule, and biofilmassociated genes make them powerful pathogens that could cause a medical nightmare. A livestock-associated CC398 lineage MRSA is well known to transfer from animals to humans and other MRSA isolates of different clonal complex groups are also known to be associated with zoonotic transfers. A human pandemic community-associated CC97 lineage MRSA harboring the antimicrobial resistance genes *mecA* and *mecC* has been shown to have originated from animals.

A comprehensive study of the emergence, dissemination, prevention and control of MRSA colonization is required to mitigate the risks to both animal and human health. Rapid advancement of whole genome sequencing technology has the great power of discriminating closely associated MRSA isolates from different sources and could be used for source tracking and differentiating between animal and human origin isolates. In addition, it can be applied to monitor the emergence and dissemination of MRSA isolated from various environments and determine the characteristics of virulence factors and evolution of multiantimicrobial resistance.

#### **Disclaimer**

The views expressed herein do not necessarily reflect those of the US Food and Drug Administration or the US Department of Health and Human Services.
