Staphylococcus aureus

Staphylococcus aureus
Scientific classification
Domain: Bacteria
Kingdom: Eubacteria
Phylum: Firmicutes
Class: Bacilli
Order: Bacillales
Family: Staphylococcaceae
Genus: Staphylococcus
Species: S. aureus
Binomial name
Staphylococcus aureus
Rosenbach 1884

Staphylococcus aureus (pronounced /ˌstæfɨlɵˈkɒkəs ˈɔri.əs/, literally the "golden cluster seed" or "the seed gold" and also known as golden staph and Oro staphira) is a facultatively anaerobic, gram-positive coccus and is the most common cause of staph infections. It is frequently part of the skin flora found in the nose and on skin. About 20% of the human population are long-term carriers of S. aureus.[1] The carotenoid pigment staphyloxanthin is responsible for S. aureus' characteristic golden colour, which may be seen in colonies of the organism. This pigment acts as a virulence factor with an antioxidant action that helps the microbe evade death by reactive oxygen species used by the host immune system. Staph organisms which lack the pigment are more easily killed by host defenses.

S. aureus can cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils (furuncles), cellulitis folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome (TSS), chest pain, bacteremia, and sepsis. Its incidence is from skin, soft tissue, respiratory, bone, joint, endovascular to wound infections. It is still one of the five most common causes of nosocomial infections, often causing postsurgical wound infections. Abbreviated to S. aureus or Staph aureus in medical literature, S. aureus should not be confused with the similarly named and similarly dangerous (and also medically relevant) species of the genus Streptococcus.

S. aureus was discovered in Aberdeen, Scotland in 1880 by the surgeon Sir Alexander Ogston in pus from surgical abscesses.[2] Each year some 500,000 patients in American hospitals contract a staphylococcal infection.[3]

Contents

Microbiology

Gram stain of S. aureus.

S. aureus is a facultatively anaerobic, Gram-positive coccus, which appears as grape-like clusters when viewed through a microscope and has large, round, golden-yellow colonies, often with hemolysis, when grown on blood agar plates.[4] The golden appearance is the etymological root of the bacteria's name; aureus means "golden" in Latin.

S. aureus is catalase-positive (meaning that it can produce the enzyme "catalase") and able to convert hydrogen peroxide (H2O2) to water and oxygen, which makes the catalase test useful to distinguish staphylococci from enterococci and streptococci. A small percentage of S. aureus can be differentiated from most other staphylococci by the coagulase test: S. aureus is primarily coagulase-positive (meaning that it can produce the enzyme "coagulase") that causes clot formation, whereas most other Staphylococcus species are coagulase-negative.[4] However, while the majority of S. aureus are coagulase-positive, some may be atypical in that they do not produce coagulase (the most common organism in patients with nosocomial bacteremia is coagulase-negative staphylococcus[5]). Incorrect identification of an isolate can impact implementation of effective treatment and/or control measures.[6]

Role in disease

Strains are responsible for food poisoning through the production of an enterotoxin and pathogenicity is also associated with coagulase positivity.

S. aureus may occur as a commensal on skin; it also occurs in the nose frequently (in about a third of the population)[7] and throat less commonly. The occurrence of S. aureus under these circumstances does not always indicate infection and, therefore, does not always require treatment (indeed, treatment may be ineffective and re-colonisation may occur). It can survive on domesticated animals such as dogs, cats, and horses, and can cause bumblefoot in chickens. It can survive for hours to days, weeks, or even months on dry environmental surfaces depending on strain.[8] It can host phages, such as Panton-Valentine leukocidin, that increase its virulence.

S. aureus can infect other tissues when barriers have been breached (e.g., skin or mucosal lining). This leads to furuncles (boils) and carbuncles (a collection of furuncles). In infants S. aureus infection can cause a severe disease staphylococcal scalded skin syndrome (SSSS).[9]

S. aureus alv infections can be spread through contact with pus from an infected wound, skin-to-skin contact with an infected person by producing hyaluronidase that destroys tissues, and contact with objects such as towels, sheets, clothing, or athletic equipment used by an infected person. Deeply penetrating S. aureus infections can be severe. Prosthetic joints put a person at particular risk for septic arthritis, and staphylococcal endocarditis (infection of the heart valves) and pneumonia, which may be rapidly spread.

Atopic dermatitis

S. aureus is extremely prevalent in atopic dermatitis patients, who are less resistant to it than other people. It often causes complications. The disease is most likely found in fertile active places including, the armpits, hair, and scalp. The large pimples that appear in those areas may cause the worst of the infection if popped. This can lead to scalded skin syndrome. A severe form of this is Ritter's disease seen in neonates.

Toxic shock syndrome and S. aureus food poisoning

Some strains of S. aureus, which produce the exotoxin TSST-1, are the causative agents of toxic shock syndrome. Some strains of S. aureus also produce an enterotoxin that is the causative agent of S. aureus gastroenteritis. The gastroenteritis is self-limiting, with the person recovering in 8–24 hours. Symptoms include nausea, vomiting, diarrhea, and abdominal pain.

Mastitis in cows

S. aureus is one of the causal agents of mastitis in dairy cows. Its large polysaccharide capsule protects the organism from recognition by the cow's immune defenses.[10]

Reproduction

S. aureus reproduces asexually. It starts this process by reproducing its DNA. The membrane stretches out and separates the DNA molecules. The cells form a hollow space that eventually divides out into two new cells. The new cell wall does not fully separate from the existing cell wall, which is why the cells are observed in clusters. This cell will eventually reproduce and cells will attach onto it.[11]

Virulence factors

Toxins

Depending on the strain, S. aureus is capable of secreting several toxins, which can be categorized into three groups. Many of these toxins are associated with specific diseases.

Superantigens
(PTSAgs) have superantigen activities that induce toxic shock syndrome (TSS). This group includes the toxin TSST-1, which causes TSS associated with tampon use. The staphylococcal enterotoxins, which cause a form of food poisoning, are included in this group.
Exfoliative toxins
EF toxins are implicated in the disease staphylococcal scalded-skin syndrome (SSSS), which occurs most commonly in infants and young children. It also may occur as epidemics in hospital nurseries. The protease activity of the exfoliative toxins causes peeling of the skin observed with SSSS.
Other toxins
Staphylococcal toxins that act on cell membranes include alpha-toxin, beta-toxin, delta-toxin, and several bicomponent toxins. The bicomponent toxin Panton-Valentine leukocidin (PVL) is associated with severe necrotizing pneumonia in children. The genes encoding the components of PVL are encoded on a bacteriophage found in community-associated methicillin-resistant S. aureus (MRSA) strains.

Protein A

Protein A is a protein that is anchored to staphylococcal peptidoglycan pentaglycine bridges (chains of five glycine residues) by the transpeptidase Sortase A.[12] Protein A is an IgG-binding protein that binds to the Fc region of an antibody. In fact, studies involving mutation of genes coding for Protein A resulted in a lowered virulence of S. aureus as measured by survival in blood, which has led to speculation that Protein A contributed virulence requires binding of antibody Fc regions.[13] Protein A in various recombinant forms has been used for decades to bind and purify a wide range of antibodies by immunoaffinity chromatography. Transpeptidases such as the sortases that are responsible for anchoring factors like Protein A to the staphylococcal peptidoglycan are being studied in hopes of developing new antibiotics to target MRSA infections.[14]

Role of pigment in virulence

Some strains of S. aureus are capable of producing staphyloxanthin - a carotenoid pigment that acts as a virulence factor. It has an antioxidant action that helps the microbe evade death by reactive oxygen species used by the host immune system. Staphyloxanthin is responsible for S. aureus' characteristic golden colour.[15] When comparing a normal strain of S. aureus with a strain modified to lack staphyloxanthin, the wildtype pigmented strain was more likely to survive incubation with an oxidizing chemical such as hydrogen peroxide than the mutant strain was. Colonies of the two strains were also exposed to human neutrophils. The mutant colonies quickly succumbed while many of the pigmented colonies survived. Wounds on mice were inoculated with the two strains. The pigmented strains created lingering abscesses. Wounds with the unpigmented strains healed quickly.

These tests suggest that the staphyloxanthin may be key to the ability of S. aureus to survive immune system attacks. Drugs designed to inhibit the bacterium's production of the staphyloxanthin may weaken it and renew its susceptibility to antibiotics.[16] In fact, because of similarities in the pathways for biosynthesis of staphyloxanthin and human cholesterol, a drug developed in the context of cholesterol-lowering therapy was shown to block S. aureus pigmentation and disease progression in a mouse infection model.[17]

Classical diagnosis

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. A Gram stain is first performed to guide the way, which should show typical gram-positive bacteria, cocci, in clusters. Second, the isolate is cultured on mannitol salt agar, which is a selective medium with 7–9% NaCl that allows S. aureus to grow, producing yellow-colored colonies as a result of mannitol fermentation and subsequent drop in the medium's pH. Furthermore, for differentiation on the species level, catalase (positive for all Staphylococcus species), coagulase (fibrin clot formation, positive for S. aureus), DNAse (zone of clearance on nutrient agar), lipase (a yellow color and rancid odor smell), and phosphatase (a pink color) tests are all done. For staphylococcal food poisoning, phage typing can be performed to determine if the staphylococci recovered from the food to determine the source of infection.

Rapid diagnosis and typing

Diagnostic microbiology laboratories and reference laboratories are key for identifying outbreaks and new strains of S. aureus. Recent genetic advances have enabled reliable and rapid techniques for the identification and characterization of clinical isolates of S. aureus in real-time. These tools support infection control strategies to limit bacterial spread and ensure the appropriate use of antibiotics. These techniques include real-time PCR and quantitative PCR and are increasingly being employed in clinical laboratories.[18][19]

Treatment and antibiotic resistance

The article Methicillin-resistant Staphylococcus aureus contains related information on this topic

The treatment of choice for S. aureus infection is penicillin; but, in most countries, penicillin-resistance is extremely common and first-line therapy is most commonly a penicillinase-resistant β-lactam antibiotic (for example, oxacillin or flucloxacillin). Combination therapy with gentamicin may be used to treat serious infections like endocarditis,[20][21] but its use is controversial because of the high risk of damage to the kidneys.[22] The duration of treatment depends on the site of infection and on severity.

Antibiotic resistance in S. aureus was uncommon when penicillin was first introduced in 1943. Indeed, the original petri dish on which Alexander Fleming of Imperial College London observed the antibacterial activity of the penicillium fungus was growing a culture of S. aureus. By 1950, 40% of hospital S. aureus isolates were penicillin-resistant; and, by 1960, this had risen to 80%.[23]

Researchers from Italy have identified a bacteriophage active against Staphylococcus aureus, including methicillin-resistant strains (MRSA), in mice and possibly humans.[24]

Mechanisms of antibiotic resistance

Staphylococcal resistance to penicillin is mediated by penicillinase (a form of β-lactamase) production: an enzyme that cleaves the β-lactam ring of the penicillin molecule, rendering the antibiotic ineffective. Penicillinase-resistant β-lactam antibiotics such as methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, and flucloxacillin are able to resist degradation by staphylococcal penicillinase.

Resistance to methicillin is mediated via the mec operon, part of the staphylococcal cassette chromosome mec (SCCmec). Resistance is conferred by the mecA gene, which codes for an altered penicillin-binding protein (PBP2a or PBP2') that has a lower affinity for binding β-lactams (penicillins, cephalosporins, and carbapenems). This allows for resistance to all β-lactam antibiotics and obviates their clinical use during MRSA infections. As such, the glycopeptide vancomycin is often deployed against MRSA.

Aminoglycoside antibiotics such as kanamycin, gentamicin, streptomycin, etc. 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 the ribosomal RNA of the bacterial 30S ribosomal subunit[25] There are three main mechanisms of aminoglycoside resistance mechanisms which are currently and widely accepted: Aminoglycoside modifying enzymes, Ribosomal mutations, and active efflux of the drug out of the bacteria.

Aminoglycoside-modifying enzymes inactivate the aminoglycoside by covalently attaching either a phosphate, nucleotide, or acetyl moiety to either the amine and/or the alcohol key functional group of the antibiotic. This changes the charge or sterically hinders the antibiotic, decreasing its ribosomal binding affinity. In S. aureus, the best-characterized aminoglycoside modifying enzyme is ANT(4')IA Aminoglycoside adenylyltransferase 4' IA. This enzyme has been solved by x-ray crystallography.[26] The enzyme is able to attach an adenyl moiety to the 4' hydroxyl group of many aminoglycosides including kamamycin and gentamicin.

Glycopeptide resistance is mediated by acquisition of the vanA gene. The vanA gene originates from the enterococci and codes for an enzyme that produces an alternative peptidoglycan to which vancomycin will not bind.

Today, S. aureus has become resistant to many commonly used antibiotics. In the UK, only 2% of all S. 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-resistant S. 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-resistant S. aureus (MRSA) was reported in England.[27]

Despite this, MRSA generally remained an uncommon finding even in hospital settings until the 1990s when there was an explosion in MRSA prevalence in hospitals where it is now endemic. [28]

MRSA infections in both the hospital and community setting are commonly treated with non-β-lactam antibiotics such as clindamycin (a lincosamine) and co-trimoxazole (also commonly known as trimethoprim/sulfamethoxazole). Resistance to these antibiotics has also led to the use of new, broad-spectrum anti-Gram-positive antibiotics such as linezolid because of its availability as an oral drug. First-line treatment for serious invasive infections due to MRSA is currently glycopeptide antibiotics (vancomycin and teicoplanin). There are number of problems with these antibiotics, such as the need for intravenous administration (there is no oral preparation available), toxicity, and the need to monitor drug levels regularly by blood tests. There are also concerns that glycopeptide antibiotics do not penetrate very well into infected tissues (this is a particular concern with infections of the brain and meninges and in endocarditis). Glycopeptides must not be used to treat methicillin-sensitive S. aureus (MSSA) as outcomes are inferior. [29]

Because of the high level of resistance to penicillins and because of the potential for MRSA to develop resistance to vancomycin, the Centers for Disease Control and Prevention have published guidelines 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 of S. aureus, treatment can be changed to flucloxacillin or even penicillin as appropriate.

Vancomycin-resistant S. aureus (VRSA) is a strain of S. aureus that has become resistant to the glycopeptides. The first case of vancomycin-intermediate S. aureus (VISA) was reported in Japan in 1996; [30] but the first case of S. aureus truly resistant to glycopeptide antibiotics was only reported in 2002. [31] Three cases of VRSA infection have been reported in the United States as of 2005. [32]

Infection control

Spread of S. aureus (including MRSA) is through human-to-human contact, although recently some veterinarians have discovered that the infection can be spread through pets , with environmental contamination thought to play a relatively unimportant part. Emphasis on basic hand washing techniques are, therefore, effective in preventing the transmission of S. aureus. The use of disposable aprons and gloves by staff reduces skin-to-skin contact and, therefore, further reduces the risk of transmission. Please refer to the article on infection control for further details.

Recently, there have been myriad reported cases of S. aureus in hospitals across America. The pathogen has had facilitated transportation in medical facilities mainly because of insufficient healthcare worker hygiene. S. aureus is an incredibly hardy bacterium, as was shown in a study where it survived on polyester for just under three months,[33] polyester being the main material used in hospital privacy curtains.

The bacterium is transported on the hands of healthcare workers who may pick up the bacteria from a seemingly healthy patient carrying a "benign" or commensal strain of S. aureus and then pass it on to the next patient being cared for. Introduction of the bacterium into the bloodstream can lead to various complications including, but not limited to, endocarditis, meningitis, and, if it is widespread, sepsis.

Ethanol has proven to be an effective topical sanitizer against MRSA. Quaternary ammonium can be used in conjunction with ethanol to increase the duration of the sanitizing action. The prevention of nosocomial infections involve routine and terminal cleaning. Nonflammable alcohol vapor in CO2 NAV-CO2 systems have an advantage as they do not attack metals or plastics used in medical environments, and do not contribute to antibacterial resistance.

An important and previously unrecognized means of community-associated MRSA colonization and transmission is during sexual contact. [34]

Staff or patients who are found to carry resistant strains of S. aureus may be required to undergo "eradication therapy," which may include antiseptic washes and shampoos (such as chlorhexidine) and application of topical antibiotic ointments (such as mupirocin or neomycin) to the anterior nares of the nose.

The nonprotein amino acid L-homoarginine is a growth inhibitor of Staphylococcus aureus as well as Candida albicans. It is assumed to be an antimetabolite of arginine.

References

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