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Vancomycin-resistant ''Staphylococcus aureus'' (VRSA) are strains of ''
Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...
'' that have acquired resistance to the
glycopeptide antibiotic Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplani ...
vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...
. Bacteria can acquire resistance genes either by random mutation or through the transfer of DNA from one bacterium to another. Resistance genes interfere with the normal antibiotic function and allow bacteria to grow in the presence of the antibiotic. Resistance in VRSA is conferred by the plasmid-mediated ''vanA'' gene and operon. Although VRSA infections are uncommon, VRSA is often resistant to other types of antibiotics and a potential threat to public health because treatment options are limited. VRSA is resistant to many of the standard drugs used to treat ''S. aureus'' infections. Furthermore, resistance can be transferred from one bacterium to another.


Mechanism of acquired resistance

Vancomycin-resistant ''Staphylococcus aureus'' was first reported in the United States in 2002. To date, documented cases of VRSA have acquired resistance through uptake of a
vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...
resistance gene cluster from ''Enterococcus'' (i.e. VRE). The acquired mechanism is typically the ''vanA'' gene and operon from a plasmid in ''Enterococcus faecium'' or ''Enterococcus faecalis''. This mechanism differs from strains of vancomycin-intermediate ''Staphylococcus aureus'' (VISA), which appear to develop elevated MICs to vancomycin through sequential mutations resulting in a thicker cell wall and the synthesis of excess amounts of D-ala-D-ala residues.


Diagnosis

The diagnosis of vancomycin-resistant ''Staphylococcus aureus'' (VRSA) is performed by performing susceptibility testing on a single ''S. aureus'' isolate to vancomycin. This is accomplished by first assessing the isolate's minimum inhibitory concentration (MIC) using standard laboratory methods, including disc diffusion, gradient strip diffusion, and automated antimicrobial susceptibility testing systems. Once the MIC is known, resistance is determined by comparing the MIC with established breakpoints. Resistant or "R" designations are assigned based on agreed upon values called breakpoints. Breakpoints are published by standards development organizations such as the U.S.
Clinical and Laboratory Standards Institute The Clinical and Laboratory Standards Institute (CLSI) is a volunteer-driven, membership-supported, not-for-profit, standards development organization. CLSI promotes the development and use of voluntary laboratory consensus standards and guidelin ...
, the
British Society for Antimicrobial Chemotherapy The British Society for Antimicrobial Chemotherapy (BSAC) is a UK-based multi-professional organisation committed to preventing infectious diseases and tackling the growing threat of drug-resistant infections – one of the top global public heal ...
and the European Committee on Antimicrobial Susceptibility Testing.


Treatment of infection

When the
minimum inhibitory concentration In microbiology, the minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible ''in vitro'' cell growth, growth of bacteria or Fungus, fungi. MIC testing is performed in both diagnosti ...
of vancomycin is , alternative antibiotics should be used. The approach is to treat with at least one agent to which the bacteria known to be susceptible by ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' testing. The agents that are used include
daptomycin Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. Daptomycin was removed from the WHO Model List of Ess ...
,
linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, va ...
,
telavancin Telavancin (trade name Vibativ by Cumberland Pharmaceuticals) is a bactericidal lipoglycopeptide for use in MRSA or other Gram-positive infections. Telavancin is a semi-synthetic derivative of vancomycin. The FDA approved the drug in September ...
,
ceftaroline Ceftaroline fosamil (INN) , brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant ''Staphylococcus ...
, and quinupristin–dalfopristin. For people with methicillin-resistant ''Staphylococcus aureus'' (MRSA)
bacteremia Bloodstream infections (BSIs) are infections of blood caused by blood-borne pathogens. The detection of microbes in the blood (most commonly accomplished by blood cultures) is always abnormal. A bloodstream infection is different from sepsis, wh ...
in the setting of vancomycin failure the Infectious Diseases Society of America recommends high-dose
daptomycin Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. Daptomycin was removed from the WHO Model List of Ess ...
, if the isolate is susceptible, in combination with another agent (e.g.,
gentamicin Gentamicin is an aminoglycoside antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis amo ...
,
rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
,
linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, va ...
,
trimethoprim/sulfamethoxazole Trimethoprim/sulfamethoxazole, sold under the trade names Bactrim, Cotrim (a short form of the British Approved Name, Co-trimoxazole) and Septra, among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacte ...
, or a beta-lactam antibiotic).


History

Three classes of vancomycin-resistant ''S. aureus'' have emerged that differ in vancomycin susceptibilities: vancomycin-intermediate ''S. aureus'' (VISA), heterogeneous vancomycin-intermediate ''S. aureus'' (hVISA), and high-level vancomycin-resistant ''S. aureus'' (VRSA).


Vancomycin-intermediate ''S. aureus'' (VISA)

Vancomycin-intermediate ''S. aureus'' (VISA) ( or ) was first identified in
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
in 1996 and has since been found in hospitals elsewhere in
Asia Asia ( , ) is the largest continent in the world by both land area and population. It covers an area of more than 44 million square kilometres, about 30% of Earth's total land area and 8% of Earth's total surface area. The continent, which ...
, as well as in
the United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...
,
France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...
, the
U.S. The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 states and a federal capital district, Washington, D.C. The 48 contiguous ...
, and
Brazil Brazil, officially the Federative Republic of Brazil, is the largest country in South America. It is the world's List of countries and dependencies by area, fifth-largest country by area and the List of countries and dependencies by population ...
. It is also termed GISA (glycopeptide-intermediate ''Staphylococcus aureus''), indicating resistance to all glycopeptide antibiotics. These bacterial strains present a thickening of the cell wall, which is believed to reduce the ability of vancomycin to diffuse into the division septum of the cell required for effective vancomycin treatment.


Vancomycin-resistant ''S. aureus'' (VRSA)

High-level vancomycin resistance in ''S. aureus'' has rarely been reported. ''
In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' and ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' experiments reported in 1992 demonstrated that vancomycin resistance genes from ''
Enterococcus faecalis ''Enterococcus faecalis'' – formerly classified as part of the group D '' Streptococcus,'' is a Gram-positive, commensal bacterium naturally inhabiting the gastrointestinal tracts of humans. Like other species in the genus '' Enterococcus'', ' ...
'' could be transferred by
gene transfer Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between organisms other than by the ("vertical") transmission of DNA from parent to offspring (reproduction). HGT is an important factor in the e ...
to ''S. aureus'', conferring high-level vancomycin resistance to ''S. aureus''. Until 2002 such a genetic transfer was not reported for wild ''S. aureus'' strains. In 2002, a VRSA strain ( or ) was isolated from a patient in Michigan. The isolate contained the ''mecA'' gene for methicillin resistance. Vancomycin MICs of the VRSA isolate were consistent with the VanA phenotype of ''
Enterococcus ''Enterococcus'' is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are Gram-positive cocci that often occur in pairs ( diplococci) or short chains, and are difficult to distinguish from streptococci on physical ch ...
'' species, and the presence of the ''vanA'' gene was confirmed by
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA (or a part of it) sufficiently to enable detailed st ...
. The DNA sequence of the VRSA ''vanA'' gene was identical to that of a vancomycin-resistant strain of ''Enterococcus faecalis'' recovered from the same catheter tip. The ''vanA'' gene was later found to be encoded within a
transposon A transposable element (TE), also transposon, or jumping gene, is a type of mobile genetic element, a nucleic acid sequence in DNA that can change its position within a genome. The discovery of mobile genetic elements earned Barbara McClinto ...
located on a
plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria and ...
carried by the VRSA isolate. This transposon, Tn''1546'', confers ''vanA''-type vancomycin resistance in enterococci. As of 2019, 52 VRSA strains have been identified in the United States, India, Iran, Pakistan, Brazil, and Portugal.


Heterogeneous vancomycin-intermediate S. aureus (hVISA)

The definition of hVISA according to Hiramatsu et al. is a strain of Staphylococcus aureus that gives resistance to vancomycin at a frequency of 10−6 colonies or even higher.


See also

*
Drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...


References


Further reading

*


External links


PubMed
{{DEFAULTSORT:Vancomycin-Resistant Staphylococcus Aureus Staphylococcaceae Bacterial diseases Antibiotic-resistant bacteria Staphylococcus