In 1880,Alexander Ogston, a Scottish surgeon, discovered thatStaphylococcus can cause wound infections after noticing groups of bacteria in pus from a surgical abscess during a procedure he was performing. He named itStaphylococcus after its clustered appearance evident under a microscope. Then, in 1884, German scientistFriedrich Julius Rosenbach identifiedStaphylococcus aureus, discriminating and separating it fromStaphylococcus albus, a related bacterium. In the early 1930s, doctors began to use a more streamlined test to detect the presence of anS. aureus infection by the means ofcoagulase testing, which enables detection of an enzyme produced by the bacterium. Prior to the 1940s,S. aureus infections were fatal in the majority of patients. However, doctors discovered that the use of penicillin could cureS. aureus infections. Unfortunately, by the end of the 1940s,penicillin resistance became widespread amongst this bacterium population and outbreaks of the resistant strain began to occur.[10]
Staphylococcus aureus can be sorted into ten dominant human lineages.[11] There are numerous minor lineages as well, but these are not seen in the population as often. Genomes of bacteria within the same lineage are mostly conserved, with the exception ofmobile genetic elements. Mobile genetic elements that are common inS. aureus include bacteriophages,pathogenicity islands,plasmids,transposons, and staphylococcal cassette chromosomes. These elements have enabledS. aureus to continually evolve and gain new traits. There is a great deal of genetic variation within theS. aureus species. A study by Fitzgerald et al. (2001) revealed that approximately 22% of theS. aureus genome is non-coding and thus can differ from bacterium to bacterium. An example of this difference is seen in the species' virulence. Only a few strains ofS. aureus are associated with infections in humans. This demonstrates that there is a large range of infectious ability within the species.[12]
It has been proposed that one possible reason for the great deal of heterogeneity within the species could be due to its reliance on heterogeneous infections. This occurs when multiple different types ofS. aureus cause an infection within a host. The different strains can secrete different enzymes or bring different antibiotic resistances to the group, increasing its pathogenic ability.[13] Thus, there is a need for a large number of mutations and acquisitions of mobile genetic elements.[citation needed]
Another notable evolutionary process within theS. aureus species is its co-evolution with its human hosts. Over time, this parasitic relationship has led to the bacterium's ability to be carried in thenasopharynx of humans without causing symptoms or infection. This allows it to be passed throughout the human population, increasing its fitness as a species.[14] However, only approximately 50% of the human population are carriers ofS. aureus, with 20% as continuous carriers and 30% as intermittent. This leads scientists to believe that there are many factors that determine whetherS. aureus is carried asymptomatically in humans, including factors that are specific to an individual person. According to a 1995 study by Hofman et al., these factors may include age, sex,diabetes, and smoking. They also determined some genetic variations in humans that lead to an increased ability forS. aureus to colonize, notably a polymorphism in theglucocorticoid receptor gene that results in largercorticosteroid production. In conclusion, there is evidence that any strain of this bacterium can become invasive, as this is highly dependent upon human factors.[15]
ThoughS. aureus has quick reproductive and micro-evolutionary rates, there are multiple barriers that prevent evolution with the species. One such barrier is AGR, which is a globalaccessory gene regulator within the bacteria. This such regulator has been linked to the virulence level of the bacteria. Loss of function mutations within this gene have been found to increase the fitness of the bacterium containing it. Thus,S. aureus must make a trade-off to increase their success as a species, exchanging reduced virulence for increased drug resistance. Another barrier to evolution is the Sau1 Type Irestriction modification (RM) system. This system exists to protect the bacterium from foreign DNA by digesting it. Exchange of DNA between the same lineage is not blocked, since they have the same enzymes and the RM system does not recognize the new DNA as foreign, but transfer between different lineages is blocked.[13]
Gram stain ofS. saprophyticus cells, which typically occur in clusters: The cell wall readily absorbs thecrystal violet stain.Key characteristics ofStaphylococcus aureus
Staphylococcus aureus (/ˌstæfɪləˈkɒkəsˈɔːriəs,-loʊ-/,[16][17]Greekσταφυλόκοκκος'grape-cluster berry',Latinaureus,'golden') is afacultative anaerobic, Gram-positivecoccal (round) bacterium also known as "golden staph" and "oro staphira".S. aureus is nonmotile and does not formspores.[18] In medical literature, the bacterium is often referred to asS. aureus,Staph aureus orStaph a..[19]S. aureus appears as staphylococci (grape-like clusters) when viewed through a microscope, and has large, round, golden-yellow colonies, often withhemolysis, when grown onblood agar plates.[20]S. aureusreproduces asexually bybinary fission. Complete separation of thedaughter cells is mediated byS. aureusautolysin, and in its absence or targeted inhibition, the daughter cells remain attached to one another and appear as clusters.[21]
Staphylococcus aureus iscatalase-positive (meaning it can produce the enzyme catalase). Catalase convertshydrogen peroxide (H 2O 2) to water and oxygen. Catalase-activity tests are sometimes used to distinguish staphylococci fromenterococci andstreptococci. Previously,S. aureus was differentiated from other staphylococci by thecoagulase test. However, not allS. aureus strains are coagulase-positive[20][22] and incorrect species identification can impact effective treatment and control measures.[23]
Natural genetic transformation is a reproductive process involving DNA transfer from one bacterium to another through the intervening medium, and the integration of the donor sequence into the recipient genome byhomologous recombination.S. aureus was found to be capable of natural genetic transformation, but only at low frequency under the experimental conditions employed.[24] Further studies suggested that the development of competence for natural genetic transformation may be substantially higher under appropriate conditions, yet to be discovered.[25]
In humans,S. aureus can be present in the upper respiratory tract, gut mucosa, and skin as a member of the normalmicrobiota.[26][27][28] However, becauseS. aureus can cause disease under certain host and environmental conditions, it is characterized as apathobiont.[26]
In the United States, MRSA infections alone are estimated to cost the healthcare system over $3.2 billion annually.[29] These infections account for nearly 20,000 deaths each year in the U.S., exceeding those caused by HIV/AIDS, Parkinson's disease, and homicide.[30] Annually, over 119,000 bloodstream infections in the U.S. are attributed toS. aureus.[31]S. aureus infections are ranked as one of the costliest healthcare-associated infections (HAIs), with each case averaging $23,000 to $46,000 in treatment and hospital resource utilization.[32]
On average, patients with MRSA infections experience a lengthened hospital stay of approximately 6 to 11 days, which drives up inpatient care costs.[33][34] The burden extends beyond direct healthcare expenses. Indirect costs, such as lost wages, reduced productivity, and long-term disability, can significantly amplify the overall economic toll. SevereS. aureus infections, including bacteremia, endocarditis, and osteomyelitis, often require prolonged recovery and rehabilitation, affecting patients' ability to return to work or perform daily activities.[35]
Hospitals also invest heavily in infection control protocols to limit the spread ofS. aureus, especially drug-resistant strains. These measures include routine screening, isolation practices, use of personal protective equipment, and antibiotic stewardship programs, which collectively contribute to rising operational costs. These necessary preventative measures can raise hospital costs by tens of thousands of dollars.[36]
Staphylococcus aureus infections canspread through contact withpus from an infected wound, skin-to-skin contact with an infected person, and contact with objects used by an infected person such as towels, sheets, clothing, or athletic equipment.Joint replacements put a person at particular risk ofseptic arthritis, staphylococcalendocarditis (infection of the heart valves), andpneumonia.[37]
Staphylococcus aureus is a significant cause of chronic biofilm infections onmedical implants, and therepressor of toxins is part of the infection pathway.[38]
Staphylococcus aureus can lie dormant in the body for years undetected. Once symptoms begin to show, the host is contagious for another two weeks, and the overall illness lasts a few weeks. If untreated, though, the disease can be deadly.[39] Deeply penetratingS. aureus infections can be severe.[citation needed]
Staphylococcus aureus is extremely prevalent in persons withatopic dermatitis (AD), more commonly known as eczema.[40] It is mostly found in fertile, active places, including the armpits, hair, and scalp. Large pimples that appear in those areas may exacerbate the infection if lacerated. Colonization ofS. aureus drives inflammation of AD.[41][40]S. aureus is believed to exploit defects in the skin barrier of persons with atopic dermatitis, triggeringcytokine expression and therefore exacerbating symptoms.[42] This can lead tostaphylococcal scalded skin syndrome, a severe form of which can be seen innewborns.[43]
The role ofS. aureus in causingitching in atopic dermatitis has been studied.[44]
Antibiotics are commonly used to target overgrowth ofS. aureus but their benefit is limited and they increase the risk ofantimicrobial resistance. For these reasons, they are only recommended for people who not only present symptoms on the skin but feel systematically unwell.[45][46][47]
Staphylococcus aureus is also responsible forfood poisoning and achieves this by generating toxins in the food, which is then ingested.[48] Itsincubation period lasts 30 minutes to eight hours,[49] with the illness itself lasting from 30 minutes to 3 days.[50] Preventive measures one can take to help prevent the spread of the disease include washing hands thoroughly with soap and water before preparing food. TheCenters for Disease Control and Prevention recommends staying away from any food if ill, and wearing gloves if any open wounds occur on hands or wrists while preparing food. If storing food for longer than 2 hours, it is recommended to keep the foodbelow 4.4 or above 60 °C (below 40 or above 140 °F).[51]
Without antibiotic treatment,S. aureus bacteremia has acase fatality rate around 80%.[3] With antibiotic treatment, case fatality rates range from 15% to 50% depending on the age and health of the patient, as well as the antibiotic resistance of theS. aureus strain.[3]
Staphylococcus aureus is often found inbiofilms formed on medical devices implanted in the body or on human tissue. It is commonly found with another pathogen,Candida albicans, forming multispecies biofilms. The latter is suspected to helpS. aureus penetrate human tissue.[9] A higher mortality is linked with multispecies biofilms.[54]
Staphylococcus aureus biofilm is the predominant cause of orthopedic implant-related infections, but is also found on cardiac implants,vascular grafts, variouscatheters, and cosmetic surgical implants.[55][56] After implantation, the surface of these devices becomes coated with host proteins, which provide a rich surface for bacterial attachment and biofilm formation. Once the device becomes infected, it must be completely removed, sinceS. aureus biofilm cannot be destroyed by antibiotic treatments.[56]
Current therapy forS. aureus biofilm-mediated infections involves surgical removal of the infected device followed by antibiotic treatment. Conventional antibiotic treatment alone is not effective in eradicating such infections.[55] An alternative to postsurgical antibiotic treatment is using antibiotic-loaded, dissolvable calcium sulfate beads, which are implanted with the medical device. These beads can release high doses of antibiotics at the desired site to prevent the initial infection.[56]
Novel treatments forS. aureus biofilm involving nano silver particles,bacteriophages, and plant-derived antibiotic agents are being studied. These agents have shown inhibitory effects againstS. aureus embedded in biofilms.[57] A class ofenzymes have been found to have biofilm matrix-degrading ability, thus may be used as biofilm dispersal agents in combination with antibiotics.[58]
Staphylococcus aureus can survive on dogs,[59] cats,[60] and horses,[61] and can causebumblefoot in chickens.[62] Some believe health-care workers' dogs should be considered asignificant source of antibiotic-resistantS. aureus, especially in times of outbreak.[59] In a 2008 study by Boost, O'Donoghue, and James, it was found that just about 90% ofS. aureus colonized within pet dogs presented as resistant to at least one antibiotic. The nasal region has been implicated as the most important site of transfer between dogs and humans.[63]
Staphylococcus aureus produces various enzymes such ascoagulase (bound and free coagulases) which facilitates the conversion of fibrinogen to fibrin to cause clots which is important in skin infections.[65]Hyaluronidase (also known as spreading factor) breaks downhyaluronic acid and helps in spreading it.Deoxyribonuclease, which breaks down the DNA, protectsS. aureus fromneutrophil extracellular trap-mediated killing.[66][67]S. aureus also produceslipase to digest lipids,staphylokinase to dissolve fibrin and aid in spread, andbeta-lactamase for drug resistance.[68]
Depending on the strain,S. aureus is capable of secreting severalexotoxins, which can be categorized into three groups. Many of these toxins are associated with specific diseases.[69]
Superantigens
Antigens known assuperantigens can inducetoxic shock syndrome (TSS). This group comprises 25 staphylococcalenterotoxins (SEs) which have been identified to date and named alphabetically (SEA–SEZ),[70] includingenterotoxin type B as well as the toxic shock syndrome toxinTSST-1 which causes TSS associated withtampon use. Toxic shock syndrome is characterized byfever,erythematous rash,low blood pressure,shock,multiple organ failure, andskin peeling. Lack of antibody to TSST-1 plays a part in the pathogenesis of TSS. Other strains ofS. aureus can produce anenterotoxin that is the causative agent of a type ofgastroenteritis. This form of gastroenteritis is self-limiting, characterized by vomiting and diarrhea 1–6 hours after ingestion of the toxin, with recovery in 8 to 24 hours. Symptoms include nausea, vomiting, diarrhea, and major abdominal pain.[71][72]
Exfoliative toxins are exotoxins implicated in the diseasestaphylococcal scalded skin syndrome (SSSS), which occurs most commonly in infants and young children. It also may occur as epidemics in hospital nurseries. Theprotease activity of the exfoliative toxins causes peeling of the skin observed with SSSS.[72]
Other toxins
Staphylococcal toxins that act on cell membranes includealpha toxin,beta toxin,delta toxin, and several bicomponent toxins. Strains ofS. aureus can hostphages, such as theprophage Φ-PVL that producesPanton-Valentine leukocidin (PVL), to increasevirulence. The bicomponent toxin PVL is associated with severe necrotizing pneumonia in children.[73][74] The genes encoding the components of PVL are encoded on abacteriophage found in community-associated MRSA strains.[citation needed]
A secretion system is a highly specialised multi-protein unit that is embedded in the cell envelope with the function of translocating effector proteins from inside of the cell to the extracellular space or into a target host cytosol. The exact structure and function of T7SS is yet to be fully elucidated. Currently, four proteins are known components ofS. aureus type VII secretion system; EssC is a large integral membraneATPase – which most likely powers the secretion systems and has been hypothesised forming part of the translocation channel. The other proteins are EsaA, EssB, EssA, that are membrane proteins that function alongside EssC to mediate protein secretion. The exact mechanism of how substrates reach the cell surface is unknown, as is the interaction of the three membrane proteins with each other and EssC.[75]
T7 dependent effector proteins
EsaD is DNAendonuclease toxin secreted byS. aureus, has been shown to inhibit growth of competitorS. aureus strainin vitro.[76] EsaD is cosecreted withchaperone EsaE, which stabilises EsaD structure and brings EsaD to EssC for secretion.[76][75] Strains that produce EsaD also co-produce EsaG, a cytoplasmic anti-toxin that protects the producer strain from EsaD's toxicity.[76]
TspA is another toxin that mediates intraspecies competition. It is a bacteriostatic toxin that has a membrane depolarising activity facilitated by itsC-terminal domain. Tsai is a transmembrane protein that confers immunity to the producer strain of TspA, as well as the attacked strains. There is genetic variability of the C-terminal domain of TspA therefore, it seems like the strains may produce different TspA variants to increase competitiveness.[77]
Toxins that play a role in intraspecies competition confers an advantage by promoting successful colonisation in polymicrobial communities such as the nasopharynx and lung by outcompeting lesser strains.[77]
There are also T7 effector proteins that play role a in pathogenesis, for example mutational studies ofS. aureus have suggested that EsxB and EsxC contribute to persistent infection in a murine abscess model.[78]
EsxX has been implicated inneutrophil lysis, therefore suggested as contributing to the evasion of host immune system. Deletion ofessX inS. aureus resulted in significantly reduced resistance to neutrophils and reduced virulence in murine skin and blood infection models.[79]
Altogether, T7SS and known secreted effector proteins are a strategy of pathogenesis by improving fitness against competitorS. aureus species as well as increased virulence via evading the innate immune system and optimising persistent infections.[citation needed]
The list ofsmall RNAs involved in the control of bacterial virulence inS. aureus is growing. This can be facilitated by factors such as increased biofilm formation in the presence of increased levels of such small RNAs.[80] For example,RNAIII,[81]SprD,[82] SprC,[83][84]RsaE,[85] SprA1,[86] SSR42,[87] ArtR,[88]SprX,Teg49,[80] and IsrR.[89]
Further investigation of icaR mRNA (mRNA coding for the repressor of the main expolysaccharidic compound of the bacteria biofilm matrix) demonstrated that the 3'UTR binding to the5' UTR can interfere with the translation initiation complex and generate a double stranded substrate forRNase III. The interaction is between the UCCCCUG motif in the 3'UTR and theShine-Dalagarno region at the 5'UTR. Deletion of the motif resulted in IcaR repressor accumulation and inhibition of biofilm development.[91] The biofilm formation is the main cause ofStaphylococcus implant infections.[92]
Biofilms are groups of microorganisms, such as bacteria, that attach to each other and grow on wet surfaces.[93] TheS. aureus biofilm is embedded in aglycocalyx slime layer and can consist ofteichoic acids, host proteins,extracellular DNA (eDNA) and sometimes polysaccharide intercellular antigen (PIA). S. aureus biofilms are important in disease pathogenesis, as they can contribute to antibiotic resistance and immune system evasion.[56]S. aureus biofilm has high resistance to antibiotic treatments and host immune response.[93] One hypothesis for explaining this is that the biofilm matrix protects the embedded cells by acting as a barrier to prevent antibiotic penetration. However, the biofilm matrix is composed with many water channels, so this hypothesis is becoming increasingly less likely, but a biofilm matrix possibly contains antibiotic‐degrading enzymes such as β-lactamases, which can prevent antibiotic penetration.[94] Another hypothesis is that the conditions in the biofilm matrix favor the formation ofpersister cells, which are highly antibiotic-resistant, dormant bacterial cells.[56]S. aureus biofilms also have high resistance to host immune response. Though the exact mechanism of resistance is unknown,S. aureus biofilms have increased growth under the presence ofcytokines produced by the host immune response.[95] Host antibodies are less effective forS. aureus biofilm due to the heterogeneousantigen distribution, where an antigen may be present in some areas of the biofilm, but completely absent from other areas.[56]
Studies in biofilm development have shown to be related to changes in gene expression. There are specific genes that were found to be crucial in the different biofilm growth stages. Two of these genes include rocD and gudB, which encode for the enzyme'sornithine-oxo-acid transaminase andglutamate dehydrogenase, which are important for amino acid metabolism. Studies have shown biofilm development rely on amino acidsglutamine andglutamate for proper metabolic functions.[96]
Protein A is anchored to staphylococcalpeptidoglycan pentaglycine bridges (chains of fiveglycine residues) by thetranspeptidasesortase A.[97] Protein A, anIgG-binding protein, binds to theFc region of anantibody. In fact, studies involving mutation of genes coding for protein A resulted in a lowered virulence ofS. aureus as measured by survival in blood, which has led to speculation that protein A-contributed virulence requires binding of antibody Fc regions.[98]
Protein A in various recombinant forms has been used for decades to bind and purify a wide range of antibodies byimmunoaffinity chromatography. Transpeptidases, such as the sortases responsible for anchoring factors like protein A to the staphylococcal peptidoglycan, are being studied in hopes of developing new antibiotics to target MRSA infections.[99]
Mutant strains ofS. aureus modified to lack staphyloxanthin are less likely to survive incubation with an oxidizing chemical, such ashydrogen peroxide, than pigmented strains. Mutant colonies are quickly killed when exposed to humanneutrophils, while many of the pigmented colonies survive.[100] In mice, the pigmented strains cause lingeringabscesses when inoculated into wounds, whereas wounds infected with the unpigmented strains quickly heal.[citation needed]
These tests suggest theStaphylococcus strains use staphyloxanthin as a defence against the normal human immune system. Drugs designed to inhibit the production of staphyloxanthin may weaken the bacterium and renew its susceptibility to antibiotics.[101] In fact, because of similarities in the pathways for biosynthesis of staphyloxanthin and humancholesterol, a drug developed in the context of cholesterol-lowering therapy was shown to blockS. aureus pigmentation and disease progression in amouse infection model.[102]
Resistance to Hypothiocyanous Acid (HOSCN)
Staphylococcus aureus has developed an adaptive mechanism to toleratehypothiocyanous acid (HOSCN), a potent oxidant produced by the human immune system.[103][104] Compared to other methicillin-resistantS. aureus (MRSA) strains and bacterial pathogens such asPseudomonas aeruginosa,Escherichia coli, andStreptococcus pneumoniae,S. aureus exhibits greater resistance to HOSCN.[105]
This resistance is linked to themerA gene, which encodes a flavoprotein disulfide reductase (FDR) enzyme.[105]S. aureus MerA shares similarities with HOSCN reductases from other bacteria, includingS. pneumoniae (50%sequence identity, 66% positives) and RclA inE. coli (50% sequence identity, 65% positives).[105] These enzymes play a crucial role inoxidative stress defense by usingNADPH as acofactor to reducedisulfide bonds, thereby mitigating theoxidative damage caused by HOSCN.[106] This mechanism enhancesS. aureus survival within the host by counteracting the immune system’s oxidative attack.[104][105]
Functional characterization of MerA has revealed that the amino acid residue Cys43 (C43) is essential for its enzymatic activity against HOSCN.[106] Additionally, the expression ofmerA inS. aureus is regulated by thehypR gene, a transcriptional suppressor that modulates the bacterial response to oxidative stress.[105]
Typical gram-positive cocci, in clusters, from a sputum sample, Gram stain
Depending upon the type of infection present, an appropriate specimen is obtained accordingly and sent to the laboratory for definitive identification by using biochemical or enzyme-based tests. AGram stain is first performed to guide the way, which should show typicalGram-positive bacteria, cocci, in clusters. Second, the isolate is cultured onmannitol salt agar, which is a selective medium with 7.5%NaCl that allowsS. aureus to grow, producing yellow-colored colonies as a result ofmannitol fermentation and subsequent drop in the medium'spH.[107][108]
Furthermore, for differentiation on the species level,catalase (positive for allStaphylococcus species),coagulase (fibrin clot formation, positive forS. aureus),DNAse (zone of clearance on DNase agar),lipase (a yellow color and rancid odor smell), andphosphatase (a pink color) tests are all done. For staphylococcal food poisoning, phage typing can be performed to determine whether the staphylococci recovered from the food were the source of infection.[109]
Diagnostic microbiology laboratories and reference laboratories are key for identifying outbreaks and new strains ofS. aureus. Recent genetic advances have enabled reliable and rapid techniques for the identification and characterization of clinical isolates ofS. aureus in real time. These tools support infection control strategies to limit bacterial spread and ensure the appropriate use of antibiotics.Quantitative PCR is increasingly being used to identify outbreaks of infection.[110][111]
When observing the evolvement ofS. aureus and its ability to adapt to each modified antibiotic, two basic methods known as "band-based" or "sequence-based" are employed.[112] Keeping these two methods in mind, other methods such asmultilocus sequence typing (MLST),pulsed-field gel electrophoresis (PFGE),bacteriophage typing, spa locus typing, and SCCmec typing are often conducted more than others.[113] With these methods, it can be determined where strains of MRSA originated and also where they are currently.[114]
With MLST, this technique of typing uses fragments of several housekeeping genes known asaroE, glpF, gmk, pta, tip, andyqiL. These sequences are then assigned a number which give to a string of several numbers that serve as the allelic profile. Although this is a common method, a limitation about this method is the maintenance of the microarray which detects newly allelic profiles, making it a costly and time-consuming experiment.[112]
With PFGE, a method which is still very much used dating back to its first success in 1980s, remains capable of helping differentiate MRSA isolates.[114] To accomplish this, the technique uses multiple gel electrophoresis, along with a voltage gradient to display clear resolutions of molecules. TheS. aureus fragments then transition down the gel, producing specific band patterns that are later compared with other isolates in hopes of identifying related strains. Limitations of the method include practical difficulties with uniform band patterns and PFGE sensitivity as a whole.[citation needed]
Spa locus typing is also considered a popular technique that uses a single locus zone in a polymorphic region ofS. aureus to distinguish any form of mutations.[114] Although this technique is often inexpensive and less time-consuming, the chance of losing discriminatory power making it hard to differentiate between MLST clonal complexes exemplifies a crucial limitation.[citation needed]
For susceptible strains, the treatment of choice forS. aureus infection ispenicillin. An antibiotic derived from somePenicilliumfungal species, penicillin inhibits the formation ofpeptidoglycan cross-linkages that provide the rigidity and strength in abacterial cell wall. The four-membered β-lactam ring of penicillin is bound to enzymeDD-transpeptidase, an enzyme that when functional, cross-links chains of peptidoglycan that form bacterial cell walls. The binding of β-lactam toDD-transpeptidase inhibits the enzyme's functionality and it can no longer catalyze the formation of the cross-links. As a result, cell wall formation and degradation are imbalanced, thus resulting in cell death. In most countries, however, penicillin resistance is extremely common (>90%), and first-line therapy is most commonly a penicillinase-resistantβ-lactam antibiotic (for example,oxacillin orflucloxacillin, both of which have the same mechanism of action as penicillin) or vancomycin, depending on local resistance patterns. Combination therapy withgentamicin may be used to treat serious infections, such asendocarditis,[115][116] but its use is controversial because of the high risk of damage to the kidneys.[117] The duration of treatment depends on the site of infection and on severity. Adjunctiverifampicin has been historically used in the management ofS aureus bacteraemia, but randomised controlled trial evidence has shown this to be of no overall benefit over standard antibiotic therapy.[118]
Antibiotic resistance inS. aureus was uncommon when penicillin was first introduced in 1943. Indeed, the original Petri dish on whichAlexander Fleming ofImperial College London observed the antibacterial activity of thePenicillium fungus was growing a culture ofS. aureus. By 1950, 40% of hospitalS. aureus isolates were penicillin-resistant; by 1960, this had risen to 80%.[119]
Methicillin-resistant Staphylococcus aureus (MRSA, often pronounced/ˈmɜːrsə/ or/ɛmɑːrɛseɪ/), is one of a number of greatly feared strains ofS. aureus which have become resistant to most β-lactam antibiotics. For this reason,vancomycin, aglycopeptide antibiotic, is commonly used to combat MRSA. Vancomycin inhibits the synthesis of peptidoglycan, but unlike β-lactam antibiotics, glycopeptide antibiotics target and bind to amino acids in the cell wall, preventing peptidoglycan cross-linkages from forming. MRSA strains are most often found associated with institutions such as hospitals, but are becoming increasingly prevalent in community-acquired infections.[citation needed]
Minor skin infections can be treated withtriple antibiotic ointment.[120] One topical agent that is prescribed ismupirocin, a protein synthesis inhibitor that is produced naturally by Pseudomonas fluorescens and has seen success for treatment of S. aureus nasal carriage.[56]
Bacterial cells ofS. aureus, which is one of the causal agents ofmastitis in dairy cows: Its large capsule protects the organism from attack by the cow's immunological defenses.
Staphylococcus aureus was found to be the second leading pathogen for deaths associated with antimicrobial resistance in 2019.[121]
Resistance to methicillin is mediated via themecoperon, part of the staphylococcal cassette chromosome mec (SCCmec). SCCmec is a family of mobile genetic elements, which is a major driving force ofS. aureus evolution.[112] Resistance is conferred by themecA gene, which codes for an alteredpenicillin-binding protein (PBP2a or PBP2') that has a lower affinity for binding β-lactams (penicillins,cephalosporins, andcarbapenems). This allows for resistance to all β-lactam antibiotics, and obviates their clinical use during MRSA infections. Studies have explained that this mobile genetic element has been acquired by different lineages in separate gene transfer events, indicating that there is not a common ancestor of differing MRSA strains.[122] One study suggests that MRSA sacrifices virulence, for example, toxin production and invasiveness, for survival and creation of biofilms[123]
Aminoglycoside antibiotics, such askanamycin,gentamicin,streptomycin, were once effective against staphylococcal infections until strains evolved mechanisms to inhibit the aminoglycosides' action, which occurs via protonated amine and/or hydroxyl interactions with theribosomal RNA of the bacterial30S ribosomal subunit.[124] Three main mechanisms of aminoglycoside resistance mechanisms are currently and widely accepted: aminoglycoside modifying enzymes, ribosomal mutations, and activeefflux of the drug out of the bacteria.[citation needed]
Aminoglycoside-modifying enzymes inactivate the aminoglycoside by covalently attaching either aphosphate,nucleotide, oracetyl moiety to either the amine or the alcohol key functional group (or both groups) of the antibiotic. This changes the charge or sterically hinders the antibiotic, decreasing its ribosomal binding affinity. InS. aureus, the best-characterized aminoglycoside-modifying enzyme is aminoglycoside adenylyltransferase 4' IA (ANT(4')IA). This enzyme has been solved byX-ray crystallography.[125] The enzyme is able to attach anadenyl moiety to the 4' hydroxyl group of many aminoglycosides, includingkanamycin and gentamicin.[citation needed]
Glycopeptide resistance is typically mediated by acquisition of thevanA gene, which originates from the Tn1546 transposon found in a plasmid inenterococci and codes for an enzyme that produces an alternativepeptidoglycan to which vancomycin will not bind.[126]
Today,S. aureus has becomeresistant to many commonly used antibiotics. In the UK, only 2% of allS. aureus isolates are sensitive to penicillin, with a similar picture in the rest of the world. The β-lactamase-resistant penicillins (methicillin, oxacillin, cloxacillin, and flucloxacillin) were developed to treat penicillin-resistantS. aureus, and are still used as first-line treatment. Methicillin was the first antibiotic in this class to be used (it was introduced in 1959), but only two years later, the first case of methicillin-resistantStaphylococcus aureus (MRSA) was reported in England.[127]
Despite this, MRSA generally remained an uncommon finding, even in hospital settings, until the 1990s, when the MRSA prevalence in hospitals exploded, and it is nowendemic.[128] Now, methicillin-resistantStaphylococcus aureus (MRSA) is not only a human pathogen causing a variety of infections, such as skin and soft tissue infection (SSTI), pneumonia, and sepsis, but it also can cause disease in animals, known as livestock-associated MRSA (LA-MRSA).[129]
MRSA infections in both the hospital and community setting are commonly treated with non-β-lactam antibiotics, such asclindamycin (a lincosamine) and co-trimoxazole (also commonly known astrimethoprim/sulfamethoxazole). Resistance to these antibiotics has also led to the use of new, broad-spectrum anti-Gram-positive antibiotics, such aslinezolid, because of its availability as an oral drug. First-line treatment for serious invasive infections due to MRSA is currentlyglycopeptide antibiotics (vancomycin andteicoplanin). A number of problems with these antibiotics occur, such as the need for intravenous administration (no oral preparation is available), toxicity, and the need to monitor drug levels regularly by blood tests. Also, glycopeptide antibiotics do not penetrate very well into infected tissues (this is a particular concern with infections of the brain andmeninges and inendocarditis). Glycopeptides must not be used to treat methicillin-sensitiveS. aureus (MSSA), as outcomes are inferior.[130]
Daptomycin works in a unique way compared to other antibiotics. It including calcium-dependent membrane binding, disruption of membrane potentia and bacterial cell death.Daptomycin is FDA-approved for treating complicated skin and soft tissue infections and bloodstream infections and right-sided infective endocarditis caused by S. aureus.[131]
Serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic.Serum-induced daptomycin tolerance is due to two independent mechanisms. The first one is the activation of the GraRS two-component system.[132] The activation is triggered by the host defenseLL-37. So that, bacteria can make more peptidoglycan to make the cell wall become thicker. This can make the tolerance of bacteria. The second one is the increase of cardiolipin abundance in the membrane.The serum-adapted bacteria can change their membrane composition. This change can reduce the binding of daptomycin to the bacteria’s membrane.[133]
Because of the high level of resistance to penicillins and because of the potential for MRSA to develop resistance to vancomycin, theU.S. Centers for Disease Control and Prevention has published guidelines[134] for the appropriate use of vancomycin. In situations where the incidence of MRSA infections is known to be high, the attending physician may choose to use a glycopeptide antibiotic until the identity of the infecting organism is known. After the infection is confirmed to be due to a methicillin-susceptible strain ofS. aureus, treatment can be changed to flucloxacillin or even penicillin, as appropriate.[citation needed]
Vancomycin-resistantS. aureus (VRSA) is a strain ofS. aureus that has become resistant to the glycopeptides. The first case of vancomycin-intermediateS. aureus (VISA) was reported in Japan in 1996;[135] but the first case ofS. aureus truly resistant to glycopeptide antibiotics was only reported in 2002.[136] Three cases of VRSA infection had been reported in the United States as of 2005.[137] At least in part the antimicrobial resistance inS. aureus can be explained by its ability to adapt. Multiple two component signal transduction pathways helpsS. aureus to express genes that are required to survive under antimicrobial stress.[138]
Among the various mechanisms that MRSA acquires to elude antibiotic resistance (e.g., drug inactivation, target alteration, reduction of permeability) there is also the overexpression ofefflux pumps. Efflux pumps are membrane-integrated proteins that are physiologically needed in the cell for the exportation of xenobiotic compounds. They are divided into six families, each of which has a different structure, function, and transport of energy. The main efflux pumps ofS. aureus are the MFS (Major Facilitator Superfamily) which includes the MdeA pump as well as the NorA pump and the MATE (Multidrug and Toxin Extrusion) to which it belongs the MepA pump. For transport, these families use an electrochemical potential and an ion concentration gradient, while the ATP-binding cassette (ABC) family acquires its energy from the hydrolysis of ATP.[citation needed]
These pumps are overexpressed by MDRS. aureus (Multidrug resistantS. aureus) and the result is an excessive expulsion of the antibiotic outside the cell, which makes its action ineffective. Efflux pumps also contribute significantly to the development of impenetrable biofilms.[citation needed]
By directly modulating efflux pumps' activity or decreasing their expression, it may be possible to modify the resistant phenotype and restore the effectiveness of existing antibiotics.[139]
About 33% of the U.S. population are carriers ofS. aureus and about 2% carryMRSA.[140] Even healthcare providers can be MRSA colonizers.[141]
The carriage ofS. aureus is an important source ofhospital-acquired infection (also called nosocomial) and community-acquired MRSA. AlthoughS. aureus can be present on the skin of the host, a large proportion of its carriage is through the anterior nares of the nasal passages[2] and can further be present in the ears.[142] The ability of the nasal passages to harbourS. aureus results from a combination of a weakened or defective host immunity and the bacterium's ability to evade host innate immunity.[143] Nasal carriage is also implicated in the occurrence of staph infections.[144]
Environmental contamination is thought to play a relatively less important part compared to direct transmission.[145] Emphasis on basichand washing techniques are, therefore, effective in preventing its transmission. The use of disposable aprons and gloves by staff reduces skin-to-skin contact, so further reduces therisk of transmission.[146]
Recently,[when?] myriad cases ofS. aureus have been reported in hospitals across America. Transmission of the pathogen is facilitated in medical settings where healthcare worker hygiene is insufficient.S. aureus is an incredibly hardy bacterium, as was shown in a study where it survived on polyester for just under three months;[147] polyester is the main material used in hospital privacy curtains.
An important and previously unrecognized means of community-associated MRSA colonization and transmission is during sexual contact.[148]
Staphylococcus aureus is killed in one minute at 78 °C and in ten minutes at 64 °C but is resistant tofreezing.[149][150]
Certain strains ofS. aureus have been described as being resistant to chlorine disinfection.[151][152]
The use of mupirocin ointment can reduce the rate of infections due to nasal carriage ofS. aureus.[153] There is limited evidence that nasal decontamination ofS. aureus using antibiotics or antiseptics can reduce the rates of surgical site infections.[154]
As of 2024, no approvedvaccine exists againstS. aureus. Earlyclinical trials have been conducted for several vaccines candidates such as Nabi's StaphVax and PentaStaph,Intercell's /Merck's V710, VRi's SA75, and others.[156]
While some of these vaccines candidates have shown immune responses, others aggravated an infection byS. aureus. To date, none of these candidates provides protection against aS. aureus infection. The development of Nabi's StaphVax was stopped in 2005 after phase III trials failed.[157] Intercell's first V710 vaccine variant was terminated during phase II/III after higher mortality and morbidity were observed among patients who developedS. aureus infection.[158]
Nabi's enhancedS. aureus vaccines candidate PentaStaph was sold in 2011 to GlaxoSmithKline Biologicals S.A.[159] The current status of PentaStaph is unclear. AWHO document indicates that PentaStaph failed in the phase III trial stage.[160]
Pfizer'sS. aureus four-antigen vaccine SA4Ag was grantedfast track designation by the U.S.Food and Drug Administration in February 2014.[163] In 2015, Pfizer has commenced a phase 2b trial regarding the SA4Ag vaccine.[164] Phase 1 results published in February 2017 showed a very robust and secure immunogenicity of SA4Ag.[165] The vaccine underwent clinical trial until June 2019, with results published in September 2020, that did not demonstrate a significant reduction in Postoperative Bloodstream Infection after Surgery.[164]
In 2015, Novartis Vaccines and Diagnostics, a former division ofNovartis and now part of GlaxoSmithKline, published promising pre-clinical results of their four-componentStaphylococcus aureus vaccine, 4C-staph.[166]
In addition to vaccine development, research is being performed to develop alternative treatment options that are effective against antibiotic resistant strains including MRSA. Examples of alternative treatments arephage therapy,antimicrobial peptides andhost-directed therapy.[167][168]
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