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Staphylococcus aureus and

Staphylococcal Disease

The Staphylococci

Staphylococci (staph) 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
more than 20 species of Staphylococcus are described in Bergey's
Manual (2001), 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, including the skin, oral cavity and
gastrointestinal tract. S epidermidis is an inhabitant of the skin.

Taxonomically, the genus Staphylococcus is in the Bacterial family


Staphylococcaceae, which includes three lesser known genera,
Gamella, Macrococcus and Salinicoccus. The best-known of its nearby
phylogenetic relatives are the members of the genus Bacillus in the
family Bacillaceae, which is on the same level as the family
Staphylococcaceae. The Listeriaceae are also a nearby 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 humans as normal flora. Staphylococcus
epidermidis may be a pathogen in the hospital environment.

Staphylococci are perfectly spherical cells about 1 micrometer in


diameter. The staphylococci grow in clusters because the cells divide
successively in three perpendicular planes with the sister cells
remaining attached to one another following each successive division.
Since the exact point of attachment of sister cells may not be within
the divisional plane, and the cells may change position slightly while
remaining attached, the result is formation of an irregular cluster of
cells.

The shape and configuration of the Gram-positive cocci helps to


distinguish staphylococci from streptococci. Streptococci are slightly
oblong cells that usually grow in chains because they divide in one
plane only, similar to a bacillus. Without a microscope, 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.
Table 1.
Important phenotypic characteristics of Staphylococcus aureus

Gram-positive, cluster-forming coccus


nonmotile, nonsporeforming facultative anaerobe
fermentation of glucose produces mainly lactic acid
ferments mannitol (distinguishes from S. epidermidis)
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 furuncules; 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.

Although methicillin-resistant Staph aureus (MRSA) have been


entrenched in hospital settings for several decades, MRSA strains have
recently emerged outside the hospital becoming known as community
associated- MRSA( (CA-MRSA) or superbug strains of the
organism, which now account for the majority of staphylococcal
infections seen in the ER or clinic.

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); (6)
membrane-damaging toxins that lyse eucaryotic cell membranes
(hemolysins, leukotoxin, leukocidin; (7) exotoxins that damage
host tissues or otherwise provoke symptoms of disease (SEA-G,
TSST, ET); and (8) inherent and acquired resistance to
antimicrobial agents.

FIGURE 2. Virulence determinants of Staphylococcus aureus

For the majority of diseases caused by 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. 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. With some staphylococcal toxins, symptoms
of human disease can be reproduced in animals with the purified
protein toxins, lending an understanding of their mechanism of action.

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 make
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.

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

Adherence to Host Cell Proteins

S. aureus cells express 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.

Invasion

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

alpha toxin (alpha-hemolysin) The best characterized and most


potent membrane-damaging toxin of S. aureus is alpha toxin. It is
expressed as a monomer that binds to the membrane of susceptible
cells. Subunits then oligomerize to form heptameric rings with a
central pore through which cellular contents leak.

In humans, platelets and monocytes are particularly sensitive to alpha


toxin. Susceptible cells have a specific receptor for alpha toxin which
allows the toxin to bind causing small pores through which monovalent
cations can pass. The mode of action of alpha hemolysin is likely by
osmotic lysis.

ß-toxin is a sphingomyelinase which damages membranes rich in this


lipid. The classical test for ß-toxin is lysis of sheep erythrocytes. The
majority of human isolates of S. aureus do not express ß-toxin. A
lysogenic bacteriophage is known to encode the toxin.

delta toxin is a very small peptide toxin produced by most strains of


S. aureus. It is also produced by S. epidermidis. The role of delta toxin
in disease is unknown.

Leukocidin is a multicomponent protein toxin produced as separate


components which act together to damage membranes. Leukocidin
forms a hetero-oligomeric transmembrane pore composed of four LukF
and four LukS subunits, thereby forming an octameric pore in the
affected membrane. Leukocidin is hemolytic, but less so than alpha
hemolysin.

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.

Staphylokinase

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 and prolong bacterial survival.
Avoidance of Host Defenses

S. aureus expresses a number of factors that have the potential to


interfere with host defense mechanisms. This includes both structural
and soluble elements of the bacterium.

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 strains isolated from infections express
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, the 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.

Leukocidin

S. aureus can express a toxin that specifically acts on


polymorphonuclear leukocytes. Phagocytosis is an important defense
against staphylococcal infection so leukocidin should be a virulence
factor.

Exotoxins

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 previously 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 alpha toxin causes septic shock, while enterotoxins


and TSST-1 are superantigens that may cause toxic shock.
Staphylococcal enterotoxins cause emesis (vomiting) when ingested
and the bacterium is a leading cause of food poisoning (intoxication).

The exfoliatin toxin causes 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 esterase and protease activity and apparently target a protein
which is involved in maintaining the integrity of the epidermis.

Superantigens: enterotoxins and toxic shock syndrome toxin

S. aureus secretes two types of toxins 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 is released 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 class II major
histocompatibility complexes of 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 be stimulated, whereas normally, antigen specificity is
also required in binding.
FIGURE 4. Superantigens and the non-specific stimulation of T cells.
Superantigens bind directly to class II major histocompatibility complexes
(MHC II) of antigen-presenting cells outside the normal antigen-binding
groove. Up to one in five T cells may be activated. Cytokines are released in
large amounts, causing the symptoms of toxic shock.

Exfoliatin toxin (ET) The exfoliatin toxin, associated with scalded


skin syndrome, causes separation within the epidermis, between the
living layers and the superficial dead layers. The separation is through
the stratum granulosum of the epidermis. This is probably why healing
occurs with little scarring although the risks of fluid loss and secondary
infections are increased. Staphylococcal exfoliative toxin B has been
shown to specifically cleave desmoglein 1, a cadherin that is found in
desmosomes in the epidermis.
Pathogenic Staphylococcus epidermidis

In contrast to S. aureus, little is known about mechanisms of


pathogenesis of S. epidermidis infections. Adherence is obviously a
crucial step in the initiation of foreign 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 S. epidermidis will bind
to fibronectin.

A characteristic of many pathogenic strains of S. 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 vancomycin-resistant strains are
increasingly-reported. The term MRSA refers to Methicillin resistant
Staphylococcus aureus. Methicillin resistance is widespread and
most methicillin-resistant strains are also multiply drug-resistant. A
plasmid associated with vancomycin resistance has been detected in
Enterococcus 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 early 1960's, staphylococcal infection was synonymous
with nosocomial infection. Gram-negative bacilli (e.g. E. coli and
Pseudomonas aeruginosa) have replaced staph as the most frequent
causes of nosocomial infections, although the staphylococci have
remained a problem, especially in surgical wounds. 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 as 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 staph infections. Indeed,
since 2003, alternatives to vancomycin have been approved for
treatment of MRSA.

MRSA
MRSA are strains of the Staphylococcus aureus that are resistant to
the action of methicillin and related beta-lactam antibiotics (e.g.
penicillin, oxacillin, amoxacillin). MRSA have evolved resistance not
only to beta-lactam antibiotics, but to several classes of antibiotics.
Some MRSA are resistant to all but one or two antibiotics, including
vancomycin. Reports of VRSA (Vancomycin-Resistant Staph aureus) or
VRSA are troublesome in the ongoing battle against staph infections.

MRSA are often sub-categorized as Hospital-Associated MRSA (HA-


MRSA) or Community-Associated MRSA (CA-MRSA), depending
upon the circumstances of acquiring disease. Based on current data,
these are distinct strains of the bacterial species.

HA-MRSA occurs most frequently among patients who undergo


invasive medical procedures or who have weakened immune systems
and are being treated in hospitals and healthcare facilities such as
nursing homes and dialysis centers. MRSA in healthcare settings
commonly causes serious and potentially life threatening infections,
such as bloodstream infections, surgical site infections or pneumonia.

In the case of HA-MRSA, patients who already have an MRSA infection


or who carry the bacteria on their bodies but do not have symptoms
(are colonized) are the most common sources of transmission. The
main mode of transmission to other patients is through human hands,
especially healthcare workers' hands. Hands may become
contaminated with MRSA bacteria by contact with infected or colonized
patients. If appropriate hand hygiene such as washing with soap and
water or using an alcohol-based hand sanitizer is not performed, the
bacteria can be spread when the healthcare worker touches other
patients.

MRSA infections that occur in otherwise healthy people who have not
been recently (within the past year) hospitalized or had a medical
procedure (such as dialysis, surgery, catheters) are categorized as
community-associated (CA-MRSA) infections. These infections are
usually skin infections, such as abscesses, boils, and other pus-filled
lesions.

About 75 percent of CA-MRSA infections are localized to skin and soft


tissue and usually can be treated effectively. However, CA-MRSA
strains display enhanced virulence, spread more rapidly and cause
more severe illness than traditional HA-MRSA infections, and can affect
vital organs leading to widespread infection (sepsis), toxic shock
syndrome and pneumonia. It is not known why some healthy people
develop CA-MRSA skin infections that are treatable whereas others
infected with the same strain develop severe, fatal infections.

Studies have shown that rates of CA-MRSA infection are growing fast.
In 1999, four children in Minnesota and North Dakota were reported to
have died from fulminant CA-MRSA infections One study of children in
south Texas found that cases of CA-MRSA increased 14-fold between
1999 and 2001. By 2007, CA-MRSA was the most frequent cause of
skin and soft-tissue infections seen in emergency departments in the
United States.

Although most MRSA cases are skin and soft-tissue infections, some
are more serious with septicemia and pneumonia. It was reported in
2005 that previously healthy adolescents without any predisposing risk
factors presented more frequently with severe Staph infections (mostly
the USA 300 strain) since 2002.

CA-MRSA skin infections have been identified among certain


populations that share close quarters or experience more skin-to-skin
contact. Examples are team athletes, military recruits, and prisoners.
However, more and more, CA-MRSA infections are being seen in the
general community as well, especially in certain geographic regions.

Also, CA-MRSA are infecting much younger people. In a study of


Minnesotans published in The Journal of the American Medical
Association, the average age of people with MRSA in a hospital or
healthcare facility was 68. But the average age of a person with CA-
MRSA was only 23.

More people in the U.S. now die from MRSA infection than from AIDS.
Methicillin-resistant Staphylococcus aureus was responsible for an
estimated 94,000 life-threatening infections and 18,650 deaths in
2005, as reported by CDC in the Oct. 17, 2007 issue of The Journal of
the American Medical Association. The national estimate is more than
double the invasive MRSA prevalence reported five years earlier. That
same year, roughly 16,000 people in the U.S. died from AIDS,
according to CDC.

While most invasive MRSA infections could be traced to a hospital stay


or some other health care exposure, about 15% of invasive infections
occurred in people with no known health care risk. Two-thirds of the
85% of MRSA infections that could be traced to hospital stays or other
health care exposures occurred among people who were no longer
hospitalized. People over age 65 were four times more likely than the
general population to get an MRSA infection. Incidence rates among
blacks were twice that of the general population, and rates were
lowest among children over the age of 4 and teens.
Host Defense against Staphylococcal Infections

Phagocytosis is the major mechanism for combating 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 phagocytes. Staphylococci may be difficult to kill after
phagocytic engulfment because they produce carotenoids and catalase
which neutralize singlet oxygen and superoxide, which are primary
phagocytic killing mechanisms within the phagolysosome.

Treatment

Hospital acquired infection is often caused by antibiotic resistant


strains (e.g. MRSA) and can only be treated with vancomycin or an
alternative. Until recently, infections acquired outside hospitals have
been treated with penicillinase-resistant ß-lactams. However, many of
the community associated (CA) staphylococcal infections are now
methicillin resistant. Particularly in Georgia, Texas, and California, the
prevalence of CA-MRSA is widespread. Over 60% of abscess isolates
from the emergency department of an Austin, Texas hospital yielded
MRSA. These organisms are uniformly resistant to penicillins and
cephalosporins. The infections have been treated with combination
therapy using sulfa drugs and minocycline or rifampin.

Vaccines

No vaccine is generally 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.
However, vaccine therapies represent a new and innovative approach
in broadening the available clinical tools against the global health
problem of community and healthcare-associated S. aureus bacterial
infections.

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.

An experimental bivalent vaccine against Staphylococcus aureus is


reported to be safe and immunogenic for approximately 40 weeks in
patients with end-stage renal disease undergoing hemodialysis. The
vaccine called StaphVAX is composed of S. aureus type 5 and 8
capsular polysaccharides conjugated to nontoxic recombinant
Pseudomonas aeruginosa exotoxin A. In randomized trials, one
injection of the vaccine was administered to 892 hemodialysis
patients. Between weeks 3 and 40, 11 cases of S. aureus bacteremia
were diagnosed in the vaccinated group compared with 26 cases in a
control group. Nearly 90% of patients receiving the vaccine generated
antibodies to the two capsular polysaccharides. A decrease in vaccine
efficacy after week 40 correlated with a decrease in S. aureus
antibodies. The investigators did not believe that use of StaphVAX
would be limited to hemodialysis patients. For example, the vaccine
might be used in cases where healthy individuals come into the
hospital for elective surgery, such as a joint replacement. Such
patients do not require protection for the rest of their lives; what they
need is protection for a short period while they are in the hospital.

The pharmaceutical company Nabi has developed a trivalent


staphylococcal polysaccharide conjugate vaccine called
TriStaph™. It contains the two main capsular types, 5 and 8, found in
the outer coating of more than 80% of S. aureus strains, conjugated
to nontoxic recombinant Pseudomonas exotoxin A. To enhance the
efficacy of this vaccine, a surface polysaccharide, 336, is added. S.
aureus Type 336 accounts for the approximately 20% of S. aureus
infections that do not form a polysaccharide capsule in the human
bloodstream. The 336 conjugate vaccine, evaluated in a phase I/II
human trial, was shown to be safe and to generate antibodies in
humans that are specific and mediate protection against 336-positive
strains of S. aureus. Together, these three polysaccharide conjugates
cover all clinically-significant serological types of S. aureus.

Since toxins are major contributors to the virulence of S. aureus


causing infections in the hospital as well as the community, Nabi
identified two vaccine candidates that cover relevant toxins. One of the
toxins in animal models is produced by almost all clinical isolates and
the other is a toxin associated with severe skin and soft tissue
infections caused by the newly emerging multi-drug resistant
community-acquired MRSA strains. Genetic engineering technology
was used to render the toxins nontoxic so they can be used safely.
Adding these two components to Tristaph produces a multi-targeted S.
aureus polysaccharide conjugate vaccine and toxoid vaccine
called PentaStaph™.

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)

pneumonia
Colonization: cell-bound (protein) adhesins
Invasion:
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)


Invasion:
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
Invasion:
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
Invasion:
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


Colonization: cell-bound (protein) adhesins
Invasion:
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