Methicillin resistant staphylococcus aureus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
The main mode of transmission of Methicillin resistant Staphylococcus aureus to other patients is through human hands, especially healthcare workers' hands. Hands may become contaminated with MRSA bacteria by contact with infected or colonized patients. If appropriate hand hygiene, such as washing with soap and water or using an alcohol-based hand sanitizer, is not performed, the bacteria can be spread when the healthcare worker touches other patients.
Staphylococcus aureus became methicillin resistant by acquiring a mecA gene, usually carried on a larger piece of DNA called a staphylococcal cassette chromosome SCCmec.
Genetics
Antimicrobial resistance is genetically based; resistance is mediated by the acquisition of extrachromosomal genetic elements containing resistance genes. Exemplary are plasmids, transposable genetic elements, and genomic islands, which are transferred between bacteria via horizontal gene transfer.[1] A defining characteristic of MRSA is its ability to thrive in the presence of penicillin-like antibiotics, which normally prevent bacterial growth by inhibiting synthesis of cell wall material. This is due to a resistance gene, mecA, which stops β-lactam antibiotics from inactivating the enzymes (transpeptidases) that are critical for cell wall synthesis.
SCCmec
Staphylococcal cassette chromosome mec (SCCmec) is a genomic island of unknown origin containing the antibiotic resistance gene mecA.[2][3] SCCmec contains additional genes beyond mecA, including the cytolysin gene psm-mec, which may suppress virulence in hospital-acquired MRSA strains.[4] SCCmec also contains ccrA and ccrB; both genes encode recombinases that mediate the site-specific integration and excision of the SCCmec element from the S. aureus chromosome.[2][3] Currently, six unique SCCmec types ranging in size from 21–67 kb have been identified;[2] they are designated types I-VI and are distinguished by variation in mec and ccr gene complexes.[5] Owing to the size of the SCCmec element and the constraints of horizontal gene transfer, a limited number of clones is thought to be responsible for the spread of MRSA infections.[2]
Different SCCmec genotypes confer different microbiological characteristics, such as different antimicrobial resistance rates.[6] Different genotypes are also associated with different types of infections. Types I-III SCCmec are large elements that typically contain additional resistance genes and are characteristically isolated from HA-MRSA strains.[3][6] Conversely, CA-MRSA is associated with types IV and V, which are smaller and lack resistance genes other than mecA.[3][6]
mecA
mecA is responsible for resistance to methicillin and other β-lactam antibiotics. After acquisition of mecA, the gene must be integrated and localized in the S. aureus chromosome.[2] mecA encodes penicillin-binding protein 2a (PBP2a), which differs from other penicillin-binding proteins as its active site does not bind methicillin or other β-lactam antibiotics.[2] As such, PBP2a can continue to catalyze the transpeptidation reaction required for peptidoglycan cross-linking, enabling cell wall synthesis in the presence of antibiotics. As a consequence of the inability of PBP2a to interact with β-lactam moieties, acquisition of mecA confers resistance to all β-lactam antibiotics in addition to methicillin.[2]
mecA is under the control of two regulatory genes, mecI and mecR1. MecI is usually bound to the mecA promoter and functions as a repressor.[3][5] In the presence of a β-lactam antibiotic, MecR1 initiates a signal transduction cascade that leads to transcriptional activation of mecA.[3][5] This is achieved by MecR1-mediated cleavage of MecI, which alleviates MecI repression.[5] mecA is further controlled by two co-repressors, BlaI and BlaR1. blaI and blaR1 are homologous to mecI and mecR1, respectively, and normally function as regulators of blaZ, which is responsible for penicillin resistance.[2][7] The DNA sequences bound by MecI and BlaI are identical;[2] therefore, BlaI can also bind the mecA operator to repress transcription of mecA.[7]
Strains
Acquisition of SCCmec in methicillin-sensitive staphylococcus aureus (MSSA) gives rise to a number of genetically different MRSA lineages. These genetic variations within different MRSA strains possibly explains the variability in virulence and associated MRSA infections.[8] The first MRSA strain, ST250 MRSA-1 originated from SCCmec and ST250-MSSA integration.[8] Historically, major MRSA clones: ST2470-MRSA-I, ST239-MRSA-III, ST5-MRSA-II, and ST5-MRSA-IV were responsible for causing hospital-acquired MRSA (HA-MRSA) infections.[8] ST239-MRSA-III, known as the Brazilian clone, was highly transmissible compared to others and distributed in Argentina, Czech Republic, and Portugal.[8]
In the UK, where MRSA is commonly called "Golden Staph", the most common strains of MRSA are EMRSA15 and EMRSA16.[9] EMRSA16 is best described by epidemiology: it originated in Kettering, England, and the full genomic sequence of this strain has been published.[10] EMRSA16 has been found to be identical to the ST36:USA200 strain, which circulates in the United States, and carries the SCCmec type II, enterotoxin A and toxic shock syndrome toxin 1 genes.[11] Under the new international typing system, this strain is now called MRSA252. EMRSA 15 is also found to be one of the common MRSA strains in Asia. Other common strains include ST5:USA100 and EMRSA 1.[12] These strains are genetic characteristics of HA-MRSA.[13]
It is not entirely certain why some strains are highly transmissible and persistent in healthcare facilities.[8] One explanation is the characteristic pattern of antibiotic susceptibility. Both the EMRSA15 and EMRSA16 strains are resistant to erythromycin and ciprofloxacin. It is known that Staphylococcus aureus can survive intracellularly,[14] such as in the nasal mucosa [15] and in the tonsil tissue.[16] Erythromycin and Ciprofloxacin are precisely the antibiotics that best penetrate intracellularly; it may be that these strains of S. aureus are therefore able to exploit an intracellular niche.
Community-acquired MRSA (CA-MRSA) strains emerged in late 1990 to 2000, infecting healthy people, who have not been in contact with health care facilities.[13] Researchers suggests that CA-MRSA did not evolve from the HA-MRSA.[13] This is further proven by molecular typing of CA-MRSA strains[17] and genome comparison between CA-MRSA and HA-MRSA, which indicate that novel MRSA strains integrated SCCmec into MSSA separately on its own.[13] By mid 2000, CA-MRSA was introduced into the health care systems and distinguishing between CA-MRSA from HA-MRSA was a difficult process.[13] Community-acquired MRSA (CA-MRSA) is more easily treated and more virulent than hospital-acquired MRSA (HA-MRSA).[13] The genetic mechanism for the enhanced virulence in CA-MRSA remains as an active area of research. The Panton-Valentine leukocidin (PVL) genes are of special interest because they are a unique feature of CA-MRSA.[8]
In the United States, most cases of CA-MRSA are caused by a CC8 strain designated ST8:USA300, which carries SCCmec type IV, Panton-Valentine leukocidin, PSM-alpha, enterotoxins Q and K,[11] and ST1:USA400.[18] ST8:USA300 strain results in skin infections, necrotizing fasciitis, and toxic shock syndrome. On the other hand, the ST1:USA400 strain results in necrotizing pneumonia and pulmonary sepsis.[8] Other community-acquired strains of MRSA are ST8:USA500 and ST59:USA1000. In many nations of the world, MRSA strains with different predominant genetic background types have come to predominate among CA-MRSA strains; USA300 easily tops the list in the U. S. and is becoming more common in Canada after its first appearance there in 2004. For example, in Australia ST93 strains are common, while in continental Europe ST80 strains predominate (Tristan et al., Emerging Infectious Diseases, 2006), which carries SCCmec type IV.[19] In Taiwan, ST59 strains, some of which are resistant to many non-beta-lactam antibiotics, have arisen as common causes of skin and soft tissue infections in the community. In a remote region of Alaska, unlike most of the continental U. S., USA300 was found rarely in a study of MRSA strains from outbreaks in 1996 and 2000 as well as in surveillance from 2004–06 (David et al., Emerg Infect Dis 2008).
In June 2011, the discovery of a new strain of MRSA was announced by two separate teams of researchers in the UK. Its genetic make-up was reportedly more similar to strains found in animals, and testing kits designed to detect MRSA were unable to identify it.[20] This MRSA strain, Clonal Complex 398 (CC398), is responsible for Livestock-associated MRSA (LA-MRSA) infections.[12] Although it is known to be more persistent in colonizing pigs and calves, there have been cases of LA-MRSA carriers with pneumonia, endocarditis, and necrotising fasciitis.[21]
Associated Diseases
MRSA is associated with the following infections:
- Skin and soft tissue infections:
References
- ↑ Jensen, S. O., Lyon, B. R. (2009). "Genetics of antimicrobial resistance in "Staphylococcus aureus"". Future Microbiology. 4: 565–582.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Lowy, F. D. (2003). "Antimicrobial resistance: the example of Staphylococcus aureus". The Journal of Clinical Investigation. 111: 1265–1273.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Monaco, M., Pantosti, A., Sanchini, A. (2007). "Mechanisms of antibiotic resistance in Staphylococcus aureus". Future Microbiology. 2: 323–334.
- ↑ Kaito, Chikara (2011). "Transcription and Translation Products of the Cytolysin Gene psm-mec on the Mobile Genetic Element SCCmec Regulate Staphylococcus aureus Virulence". PLoS Pathogens. 7 (2): e1001267. doi:10.1371/journal.ppat.1001267. Unknown parameter
|month=ignored (help); Unknown parameter|coauthors=ignored (help) - ↑ 5.0 5.1 5.2 5.3 Jensen, S. O., Lyon, B. R. (2009). "Genetics of antimicrobial resistance in Staphylococcus aureus". Future Microbiology. 4: 565–582.
- ↑ 6.0 6.1 6.2 Kuo, S., Chiang, M., Lee, W., Chen, L., Wu, H., Yu, K., Fung, C., Wang, F. (2012). "Comparison of microbiological and clinical characteristics based in SCCmec typing in patients with community-onset meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia". International Journal of Antimicrobial Agents. 39: 22–26.
- ↑ 7.0 7.1 Berger-Bächi, B. (1999). "Genetic basis of methicillin resistance in Staphylococcus aureus". Cellular and Molecular Life Sciences. 56: 764–770.
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Gordon, Rachel J.; Lowy, Franklin D. (2008). "Pathogenesis of Methicillin‐ResistantStaphylococcus aureusInfection". Clinical Infectious Diseases. 46 (S5): S350–S359. doi:10.1086/533591. ISSN 1058-4838.
- ↑ Johnson AP, Aucken HM, Cavendish S; et al. (2001). "Dominance of EMRSA-15 and -16 among MRSA causing nosocomial bacteraemia in the UK: analysis of isolates from the European Antimicrobial Resistance Surveillance System (EARSS)". J Antimicrob Chemother. 48 (1): 143–4. doi:10.1093/jac/48.1.143. PMID 11418528.
- ↑ Holden MTG, Feil EJ, Lindsay JA; et al. (2004). "Complete genomes of two clinical Staphylococcus aureus strains: Evidence for the rapid evolution of virulence and drug resistance". Proc Natl Acad Sci USA. 101 (26): 9786–91. doi:10.1073/pnas.0402521101. PMC 470752. PMID 15213324. Unknown parameter
|issues=ignored (help) - ↑ 11.0 11.1 Diep B, Carleton H, Chang R, Sensabaugh G, Perdreau-Remington F (2006). "Roles of 34 virulence genes in the evolution of hospital- and community-associated strains of methicillin-resistant Staphylococcus aureus". J Infect Dis. 193 (11): 1495–503. doi:10.1086/503777. PMID 16652276.
- ↑ 12.0 12.1 Stefani, Stefania; Chung, Doo Ryeon; Lindsay, Jodi A.; Friedrich, Alex W.; Kearns, Angela M.; Westh, Henrik; MacKenzie, Fiona M. (2012). "Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods". International Journal of Antimicrobial Agents. doi:10.1016/j.ijantimicag.2011.09.030. ISSN 0924-8579.
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 Calfee, David P. (2011). "The Epidemiology, Treatment, and Prevention of Transmission of Methicillin-Resistant Staphylococcus aureus". Journal of Infusion Nursing. 34 (6): 359–364. doi:10.1097/NAN.0b013e31823061d6. ISSN 1533-1458.
- ↑ von Eiff C, Becker K, Metze D; et al. (2001). "Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier's disease". Clin Infect Dis. 32 (11): 1643–7. doi:10.1086/320519. PMID 11340539.
- ↑ Clement S, Vaudaux P, François P; et al. (2005). "Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis". J Infect Dis. 192 (6): 1023–8. doi:10.1086/432735. PMID 16107955.
- ↑ Zautner AE, Krause M, Stropahl G; et al. (2010). Bereswill, Stefan, ed. "Intracellular persisting Staphylococcus aureus is the major pathogen in recurrent tonsillitis". PloS One. 5 (3): e9452. doi:10.1371/journal.pone.0009452. PMC 2830486. PMID 20209109.
- ↑ Daum, Robert S. (2007). "Skin and Soft-Tissue Infections Caused by Methicillin-ResistantStaphylococcus aureus". New England Journal of Medicine. 357 (4): 380–390. doi:10.1056/NEJMcp070747. ISSN 0028-4793. PMID 17652653.
- ↑ Wang R, Braughton KR, Kretschmer D; et al. (2007). "Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA". Nat. Med. 13 (12): 1510–4. doi:10.1038/nm1656. PMID 17994102. Unknown parameter
|month=ignored (help) - ↑ Gould, Ian M.; David, Michael Z.; Esposito, Silvano; Garau, Javier; Lina, Gerard; Mazzei, Teresita; Peters, Georg (2012). "New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance". International Journal of Antimicrobial Agents. 39 (2): 96–104. doi:10.1016/j.ijantimicag.2011.09.028. ISSN 0924-8579.
- ↑ Ahlstrom, Dick (2011-06-03). "New strain of MRSA superbug discovered in Dublin hospitals". The Irish Times.
- ↑ Graveland, Haitske; Duim, Birgitta; van Duijkeren, Engeline; Heederik, Dick; Wagenaar, Jaap A. (2011). "Livestock-associated methicillin-resistant Staphylococcus aureus in animals and humans". International Journal of Medical Microbiology. 301 (8): 630–634. doi:10.1016/j.ijmm.2011.09.004. ISSN 1438-4221.