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Staphylococci are Gram-positive spherical bacteria that occur in microscopic clusters resembling grapes. Bacteriological culture of the nose and skin of normal humans invariably yields staphylococci. In 1884, Rosenbach described the two pigmented colony types of staphylococci and proposed the appropriate nomenclature: Staphylococcus aureus (yellow) and Staphylococcus albus (white). The latter species is now named Staphylococcus epidermidis. Although nineteen species of Staphylococcus are described in Bergey's Manual (1992), only Staphylococcus aureus and Staphylococcus epidermidis are significant in their interactions with humans. S. aureus colonizes mainly the nasal passages, but it may be found regularly in most other anatomical locales. S epidermidis is an inhabitant of the skin.

The staphylococci are in the Bacterial family Micrococcaceae, but they are phylogenetically unrelated to any other genera in the family. Staphylococcus aureus forms a fairly large yellow colony on rich medium, S. epidermidis has a relatively small white colony. S. aureus is often hemolytic on blood agar; S. epidermidis is non hemolytic. Staphylococci are facultative anaerobes that grow by aerobic respiration or by fermentation that yields principally lactic acid. The bacteria are catalase-positive and oxidase-negative. S. aureus can grow at a temperature range of 15 to 45 degrees and at NaCl concentrations as high as 15 percent. Nearly all strains of S. aureus produce the enzyme coagulase: nearly all strains of S. epidermidis lack this enzyme. S. aureus should always be considered a potential pathogen; most strains of S. epidermidis are nonpathogenic and may even play a protective role in their host as normal flora. Staphylococcus epidermidis may be a pathogen in the hospital environment.

Staphylococci are perfectly spherical cells about 1 micrometer in diameter. They grow in clusters because staphylococci divide in two planes. The configuration of the cocci helps to distinguish staphylococci from streptococci, which are slightly oblong cells that usually grow in chains (because they divide in one plane only). The catalase test is important in distinguishing streptococci (catalase-negative) from staphylococci, which are vigorous catalase-producers. The test is performed by adding 3% hydrogen peroxide to a colony on an agar plate or slant. Catalase-positive cultures produce O2 and bubble at once. The test should not be done on blood agar because blood itself contains catalase.

STAPH1 picture

FIGURE 1. Gram stain of Staphylococcus aureus in pustular exudate

Table 1. Important phenotypic characteristics of Staphylococcus aureus

Gram-positive, cluster-forming coccus

nonmotile, nonsporeforming facultative anaerobe

fermentation of glucose produces mainly lactic acid

catalase positive

coagulase positive

golden yellow colony on agar.

normal flora of humans found on nasal passages, skin and mucous membranes

pathogen of humans, causes a wide range of suppurative infections, as well as food poisoning and toxic shock syndrome

Pathogenesis of S. aureus infections

Staphylococcus aureus causes a variety of suppurative (pus-forming) infections and toxinoses in humans. It causes superficial skin lesions such as boils, styes and furunculosis; more serious infections such as pneumonia, mastitis, phlebitis, meningitis, and urinary tract infections; and deep-seated infections, such as osteomyelitis and endocarditis. S. aureus is a major cause of hospital acquired (nosocomial) infection of surgical wounds and infections associated with indwelling medical devices.S. aureus causes food poisoning by releasing enterotoxins into food, and toxic shock syndrome by release of superantigens into the blood stream.

S. aureus expresses many potential virulence factors:

  1. surface proteins that promote colonization of host tissues

  2. invasins that promote bacterial spread in tissues (leukocidin, kinases, hyaluronidase)

  3. surface factors that inhibit phagocytic engulfment (capsule, Protein A)

  4. biochemical properties that enhance their survival in phagocytes (carotenoids, catalase production)

  5. immunological disguises (Protein A, coagulase, clotting factor)

  6. membrane-damaging toxins that lyse eukaryotic cell membranes (hemolysins, leukotoxin, leukocidin

  7. exotoxins that damage host tissues or otherwise provoke symptoms of disease (SEA-G, TSST, ET

  8. inherent and acquired resistance to antimicrobial agents.

STAPH2 picture

FIGURE 2. Virulence determinants of Staphylococcus aureus

For the majority of diseases caused by this S. aureus, pathogenesis is multifactorial, so it is difficult to determine precisely the role of any given factor. However, there are correlations between strains isolated from particular diseases and expression of particular virulence determinants, which suggests their role in a particular diseases. With some exotoxins, symptoms of a human disease can be reproduced in animals with the pure proteins. The application of molecular biology has led to advances in unraveling the pathogenesis of staphylococcal diseases. Genes encoding potential virulence factors have been cloned and sequenced, and many protein toxins have been purified. Human staphylococcal infections are frequent, but usually remain localized at the portal of entry by the normal host defenses. The portal may be a hair follicle, but usually it is a break in the skin which may be a minute needle-stick or a surgical wound. Foreign bodies, including sutures, are readily colonized by staphylococci, which may makes infections difficult to control. Another portal of entry is the respiratory tract. Staphylococcal pneumonia is a frequent complication of influenza. The localized host response to staphylococcal infection is inflammation, characterized by an elevated temperature at the site, swelling, the accumulation of pus, and necrosis of tissue. Around the inflamed area, a fibrin clot may form, walling off the bacteria and leukocytes as a characteristic pus-filled boil or abscess. More serious infections of the skin may occur, such as furuncles or impetigo. Localized infection of the bone is called osteomyelitis. Serious consequences of staphylococcal infections occur when the bacteria invade the blood stream. A resulting septicemia may be rapidly fatal; a bacteremia may result in seeding other internal abscesses, other skin lesions, or infections in the lung, kidney, heart, skeletal muscle or meninges.

STAPH3 picture

FIGURE 3. Sites of infection and diseases caused by Staphylococcus aureus

Adherence to Host Cell Proteins

S aureus cells express on their surface proteins that promote attachment to host proteins such as laminin and fibronectin that form the extracellular matrix of epithelial and endothelial surfaces. In addition, most strains express a fibrin/fibrinogen binding protein (clumping factor) which promotes attachment to blood clots and traumatized tissue. Most strains of S. aureus express both fibronectin and fibrinogen-binding proteins. In addition, an adhesin that promotes attachment to collagen has been found in strains that cause osteomyelitis and septic arthritis. Interaction with collagen may also be important in promoting bacterial attachment to damaged tissue where the underlying layers have been exposed.

Evidence that staphylococcal matrix-binding proteins are

virulence factors has come from studying defective mutants in adherence assays. Mutants defective in binding to fibronectin and to fibrinogen have reduced virulence in a rat model for endocarditis, and mutants lacking the collagen-binding protein have reduced virulence in a mouse model for septic arthritis, suggesting that bacterial colonization is ineffective. Furthermore, the isolated ligand-binding domain of the fibrinogen, fibronectin and collagen receptors strongly blocks attachment of bacterial cells to the corresponding host proteins.


The invasion of host tissues by staphylococci apparently involves the production of a huge array of extracellular proteins, some of which may occur also as cell-associated proteins. These proteins are described below with some possible explanations for their role in invasive process.

Membrane-damaging toxins

a -toxin

The best characterized and most potent membrane-damaging toxinof S aureus is a-toxin. It is expressed as a monomer that binds to the membrane of susceptible cells. Subunits then oligomerize to form hexameric rings with a central pore through which cellular contents leak. Susceptible cells have a specific receptor for a-toxin which allows the toxin to bind causing small pores through which monovalent cations can pass. In humans, platelets and monocytes are particularly sensitive to a-toxin. After binding the toxin, a complex series of secondary reactions ensues, causing release of cytokines that trigger production of inflammatory mediators. These events cause the symptoms of septic shock that occur during severe infections caused by S aureus.


-toxin is a sphingomyelinase which damages membranes rich in this lipid. The classical test for -toxin is lysis of sheep erythrocytes. The majority of human isolates of S aureus do not express -toxin. A lysogenic bacteriophage is known to encode the toxin.


The d-toxin is a very small peptidetoxin produced by most strains of S aureus. It is also produced by S epidermidis. The role of d-toxin in disease is unknown.

g-toxin and leukocidin

The g-toxin (also called leukotoxin) and leukocidin are two-component protein toxins that damage membranes of susceptible cells. The proteins are expressed separately but act together to damage membranes. There is no evidence that they form multimers prior to insertion into membranes. Leukocidin is distinct from the leukotoxin and it is the product of a separate gene locus.

Leukotoxin is hemolytic whereas leukocidin is non-hemolytic. Only 2% of all of S. aureus isolates express leukocidin, but nearly 90% of the strains isolated from severe dermonecrotic lesions express this toxin, which suggests that it is an important factor in necrotizing skin infections.

Coagulase and clumping factor

Coagulase is an extracellular protein which binds to prothrombin in the host to form a complex called staphylothrombin. The protease activity characteristic of thrombin is activated in the complex, resulting in the conversion of fibrinogen to fibrin. Coagulase is a traditional marker for identifying S aureus in the clinical microbiology laboratory. However, there is no overwhelming evidence that it is a virulence factor, although it is reasonable to speculate that the bacteria could protect themselves from phagocytic and immune defenses by causing localized clotting.

There is some confusion in the literature concerning coagulase and clumping factor, the fibrinogen-binding determinant on the S.aureus cell surface. Partly the confusion results from the fact that a small amount of coagulase is tightly bound on the bacterial cell surface where it can react with prothrombin leading to fibrin clotting. However, genetic studies have shown unequivocally that coagulase and clumping factor are distinct entities. Specific mutants lacking coagulase retain clumping factor activity, while clumping factor mutants express coagulase normally.


Many strains of S aureus express a plasminogen activator called staphylokinase. This factor lyses fibrin.The genetic determinant is associated with lysogenic bacteriophages. A complex formed between staphylokinase and plasminogen activates plasmin-like proteolytic activity which causes dissolution of fibrin clots. The mechanism is identical to streptokinase, which is used in medicine to treat patients suffering from coronary thrombosis. As with coagulase there is no strong evidence that staphylokinase is a virulence factor, although it seems reasonable to imagine that localized fibrinolysis might aid in bacterial spreading.

Other extracellular enzymes

S aureus can express proteases, a lipase, a deoxyribonuclease (DNase) and a fatty acid modifying enzyme (FAME). The first three probably provide nutrients for the bacteria, and it is unlikely that they have anything but a minor role in pathogenesis. However, the FAME enzyme may be important in abscesses, where it could modify anti-bacterial lipids andprolong bacterial survival.


Avoidance of Host Defenses

S aureus expresses a number of factors that have the potential to interfere with host defense mechanisms.

Capsular Polysaccharide

The majority of clinical isolates of S aureus express a surface polysaccharide of either serotype 5 or 8. This has been called a microcapsule because it can be visualized only by electron microscopy unlike the true capsules of some bacteria which are readily visualized by light microscopy. S aureus isolated from infections expresses high levels of the polysaccharide but rapidly lose the ability when cultured in the laboratory. The function of the capsule in virulence is not entirely clear. Although it does impede phagocytosis in the absence of complement, it also impedes colonization of damaged heart valves, perhaps by masking adhesins.

Protein A

Protein A is a surface protein of S aureus which

binds IgG molecules by their Fc region. In serum, bacteria will bind IgG molecules in the wrong orientation on their surface which disrupts opsonization and phagocytosis. Mutants of S aureus lacking protein A are more efficiently phagocytosed in vitro, and mutants in infection models have diminished virulence.



S. aureus can express a toxin that specifically acts on polymorphonuclear leukocytes. Phagocytosis is an importantdefense against staphylococcal infection so leukocidin should bea virulence factor.


S aureus can express several different types of protein toxins which are probably responsible for symptoms during infections. Those which damage the membranes of cells were discussed above under Invasion. Some will lyse erythrocytes, causing hemolysis, but it is unlikely that hemolysis is a relevant determinant of virulence in vivo. Leukocidin causes membrane damage to leukocytes, but is not

hemolytic. Systemic release of a-toxin causes septic shock, while enterotoxins and TSST-1 are superantigens that may cause toxic shock. Staphylococcal enterotoxins cause emesis (vomiting) when ingested The exfoliatin toxin, associated with scalded skin syndrome, causes separation of the dermal and epidermal layers of the skin by an unknown mechanism


Superantigens: enterotoxins and toxic shock syndrome toxin

S aureus secretes two types of toxin with superantigen activity, enterotoxins, of which there are six antigenic types (named SE-A, B, C, D, E and G), and toxic shock syndrome toxin (TSST-1). Enterotoxins cause diarrhea and vomiting when ingested and are responsible for staphylococcal food poisoning. TSST-1 is expressed systemically and is the cause of toxic shock syndrome (TSS). When expressed systemically, enterotoxins can also cause toxic shock syndrome. In fact, enterotoxins B and C cause 50% of non-menstrual cases of TSS. TSST-1 is weakly related to enterotoxins, but it does not have emetic activity. TSST-1 is responsible for 75% of TSS, including all menstrual cases. TSS can occur as a sequel to any staphylococcal infection if an enterotoxin or TSST-1 isreleased systemically and the host lacks appropriate neutralizing antibodies.

Superantigens stimulate T cells non-specifically without normal antigenic recognition (Figure 4). Up to one in five T cells may be activated, whereas only 1 in 10,000 are stimulated during a usual antigen presentation. Cytokines are released in large amounts, causing the symptoms of TSS. Superantigens bind directly to antigen-presenting cells outside the conventional antigen-binding grove. This complex recognizes only the Vb element of the T cell receptor. Thus any T cell with the appropriate Vb element can bestimulated, whereas normally antigen specificity is also required in binding.

STAPH4 picture

FIGURE 4. Superantigens and the non-specific stimulation of T cells

Exfoliatin toxin (ET)

This toxin causes the scalded skin syndrome in neonates, which results in widespread blistering and loss of the epidermis. There are two antigenically distinct forms of the toxin, ETA and ETB. The toxins have a specific esterase activity, but it is not clear how this would causes epidermal splitting. There is some evidence that the toxins have protease activity, so it is also possible that the toxins target a very specific protein which is involved in maintaining the integrity of the epidermis. Pathogenic Staphylococcus epidermidis In contrast to S. aureus, little is known aboutmechanisms of pathogenesis of S. epidermidis infections.

Adherence is obviously a crucial step in the initiation offoreign body infections. Bacteria-plastic interactions are probably important in colonization of catheters, and a polysaccharide adhesion (PS/A) has been identified. In addition, when host proteins deposit on the implanted device Sepidermidis will bind to fibronectin. A characteristic of many pathogenic strains ofS. epidermidis is the production of a slime resulting in biofilm formation. The slime is predominantly a secreted teichoic acid, normally found in the cell wall of the staphylococci. This ability to form a biofilm on the surface of a prosthetic device is probably a significant determinant of virulence for these bacteria.

Resistance of Staphylococci to Antimicrobial Drugs

Hospital strains of S aureus are usually resistant to a variety of different antibiotics. A few strains are resistant to all clinically useful antibiotics except vancomycin, and, rarely, vancomycin-resistant strains have been reported. The term MRSA refers to Methicillin resistant Staphylococcus aureus. Methicillin resistance is widespread and most methicillin-resistant strains are also multiply resistant. A plasmid associated with vancomycin resistance has been detected in the enterococci (Streptococcus faecalis), which can be transferred to S. aureus in the laboratory, and it is speculated that this transfer may occur naturally (e.g. in the gastrointestinal tract). In addition, S aureus exhibits resistance to antiseptics and disinfectants, such as quaternary ammonium compounds, which may aid its survival in the hospital environment.

Staphylococcal disease has been a perennial problem in the hospital environment since the beginning of the antibiotic era. During the 1950's and early1960's, staphylococcal infection was synonymous with nosocomial infection. Gram-negative bacilli (e.g. E. coli and Pseudomonas aeruginosa) have replaced the staphylococci as the most frequent causes of nosocomial infections, although the staphylococci have remained a problem. S aureus responded to the introduction of antibiotics by the usual bacterial means to develop drug resistance: (1) mutation in chromosomal genes followed by selection of resistant strains and (2) acquisition of resistance genes as extrachromosomal plasmids, transducing particles, transposons, or other types of DNA inserts. S. aureus expresses its resistance to drugs and antibiotics through a variety of mechanisms.

Beginning with the use of the penicillin in the 1940's, drug resistance has developed in the staphylococci within a very short time after introduction of an antibiotic into clinical use. Some strains are now resistant to most conventional antibiotics, and there is concern that new antibiotics have not been forthcoming. New strategies in the pharmaceutical industry to find antimicrobial drugs involve identifying potential molecular targets in cells (such the active sites of enzymes involved in cell division), then developing inhibitors of the specific target molecule. Hopefully, this approach will turn up new antimicrobial agents for the battle against staphylococcal infections.

Host Defense against Staphylococcal Infections

Phagocytosis is the major mechanism for combatting staphylococcal infection. Antibodies are produced which neutralize toxins and promote opsonization. However, the bacterial capsule and protein A may interfere with phagocytosis. Biofilm growth on implants is also impervious to phagocytosis.


Infections acquired outside hospitals can usually be treated with penicillinase-resistant -lactams. Hospital acquired infection is often caused by antibiotic resistant strains and can only be treated with vancomycin.


No vaccine is available that stimulates active immunity against staphylococcal infections in humans. A vaccine based on fibronectin binding protein induces protective immunity against mastitis in cattle and might also be used as a vaccine in humans. Hyperimmune serum or monoclonal antibodies directed towards surface components (e.g., capsular polysaccharide or surface protein adhesions) could theoretically prevent bacterial adherence and promote phagocytosis by opsonization of bacterial cells. Also, human hyperimmune serum could be given to hospital patients before surgery as a form of passive immunization. When the precise molecular basis of the interactions between staphylococcal adhesins and host tissue receptors is known it might be possible to design compounds that block the interactions and thus prevent bacterial colonization. These could be administered systemically or topically.

Table 2. Possible virulence determinants expressed in the pathogenesis of Staphylococcus aureus infections

boils and pimples (folliculitis)
Colonization: cell-bound (protein) adhesins
Invasion: Invasins: staphylokinase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin
Resistance to immune responses: coagulase
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)
Colonization: cell-bound (protein) adhesins
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: Cytotoxic toxins (hemolysins and leukocidin)
food poisoning (emesis or vomiting)
Toxigenesis: Enterotoxins A-G
septicemia (invasion of the bloodstream)
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)
osteomyelitis (invasion of bone)
Colonization: cell-bound (protein) adhesins
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)
toxic shock syndrome
Colonization: cell-bound (protein) adhesins
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: TSST toxin, Enterotoxins A-G
surgical wound infections
Colonization: cell-bound (protein) adhesins
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, protein A, leukocidin, hemolysins, carotenoids, superoxide dismutase, catalase, growth at low pH
Resistance to immune responses: coagulase, protein A, antigenic variation
Toxigenesis: cytotoxic toxins (hemolysins and leukocidin)
scalded skin syndrome (analogous to scarlet fever)
Colonization: cell-bound (protein) adhesins
Invasins: staphylokinase, hyaluronidase
Other extracellular enzymes (proteases, lipases, nucleases, collagenase, elastase. etc.)
Resistance to phagocytosis: coagulase, leukocidin, hemolysins
Resistance to immune responses: coagulase, antigenic variation
Toxigenesis: Exfoliatin toxin
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