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Gram-Positive Cocci

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Yasmeen Yahya

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Transcript of Gram-Positive Cocci

Gram-Positive Cocci
chapter 15
AP Dr. Said S. Al-Ghora
Introduction.
Staphylococcus.
Streptococcus.
Streptococcus pneumoniae.
CHAPTER CONTENTS
There are two medically important genera of gram-positive cocci:
Staphylococcus
and
Streptococcus
.

Two of the most important human pathogens,
Staphylococcus aureus
and
Streptococcus pyogenes
, are described in this chapter. Staphylococci and streptococci are nonmotile and do not form spores.
Both staphylococci and streptococci are gram-positive cocci, but they are distinguished by two main criteria:

(1)
Microscopically
, staphylococci appear in grapelike clusters, whereas streptococci are in chains.

(2)
Biochemically
, staphylococci produce
catalase
(i.e., they degrade hydrogen peroxide), whereas streptococci do not.
INTRODUCTION
STAPHYLOCOCCUS
STREPTOCOCCUS
Important Properties
Staphylococci are spherical gram-positive cocci arranged in irregular
grapelike
clusters. All staphylococci produce
catalase
, whereas no streptococci do. Catalase is an important virulence factor because H2O2 is microbicidal and its degradation limits the ability of neutrophils to kill.
Three species of staphylococci are human pathogens:
Sta. aureus, Sta. epidermidis,
and
Sta. saprophyticus

Staphylococcus aureus
Greek, "grape-cluster berry", Latin aureus, "golden"

It is a gram-positive coccal (round) bacterium also known as "golden staph".
Behind The Name
It is one of the most common causes of hospital-acquired pneumonia, septicemia, and surgical-wound infections.

It is the most common cause of bacterial conjunctivitis.
Sta. aureus is distinguished from other species primarily by
coagulase
production. Coagulase is an enzyme that causes plasma to clot by activating prothrombin to formthrombin. Thrombin then catalyzes the activation of fibrinogen to form the fibrin clot.
Sta. aureus produces a carotenoid pigment called
staphyloxanthin
, which imparts a golden color to its colonies. This pigment enhances the pathogenicity of the organism by inactivating the microbicidal effect of superoxides and other reactive oxygen species within neutrophils.
Sta. aureus usually
ferments mannitol
and
hemolyzes red blood cells
, whereas other species don't.
Hemolysis of red cells by hemolysins produced by Sta. aureus is the source of
iron

required for growth of the organism. The iron in hemoglobin is recovered by the bacteria and utilized in the synthesis of cytochrome enzymes used to produce energy.

Remember;

Which

Type

Of

Hemolysis?
Sta. aureus has several important cell wall components and antigens:
(1) Protein A is the major protein in the cell wall. It is an important virulence factor because it binds to the Fc portion of IgG at the complement-binding site, thereby
preventing the activation of complement.
As a consequence, no C3b is produced, and the opsonization and phagocytosis of the organisms are greatly reduced. Protein A is used in certain tests in the clinical laboratory because it binds to IgG and forms a
“coagglutinate”
with antigen–antibody complexes. The coagulase- negative staphylococci do not produce protein A.
Protein A
(2) Teichoic acids are polymers of ribitol phosphate. They mediate adherence of the staphylococci to mucosal cells. Lipoteichoic acids play a role in the
induction of septic shock
by inducing cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) from macrophages
Teichoic Acids
(3) Polysaccharide capsule is also an important virulence factor. There are 11 serotypes based on the antigenicity of the capsular polysaccharide, but types 5 and 8 cause 85% of infections. Some strains of
Sta. aureus
are coated with a small amount of polysaccharide capsule, called a microcapsule. The capsule is
poorly immunogenic
, which has made producing an effective vaccine difficult.
Polysaccharide Capsule
(4) Surface receptors for specific staphylococcal bacteriophages permit the
“phage typing”
of strains for epidemiologic purposes. Teichoic acids make up part of these receptors.
Surface Receptors
(5) The peptidoglycan of Sta. aureus has
endotoxin-like
properties (i.e., it can stimulate macrophages to produce cytokines and can activate the complement and coagulation cascades). This explains the ability of Sta. aureus to cause the clinical findings of septic shock yet not possess endotoxin.
Peptidoglycan
Transmission
The nose is the main site of colonization of Sta. aureus.

The skin, especially of hospital personnel and patients, is also a common site of Sta. aureus colonization. (hand washing)

Sta. aureus is also found in the vagina of approximately 5% of women. (TSS)

Additional sources of staphylococcal infection are shedding from human lesions and fomites such as towels and clothing contaminated by these lesions.
Pathogenesis
Sta. aureus causes disease both by producing
toxins

and by inducing
pyogenic inflammation
. The typical lesion of Sta. aureus infection is an
abscess
. Abscesses undergo central necrosis and usually drain to the outside (e.g., furuncles and boils), but organisms may disseminate via the bloodstream as well.
Foreign bodies
, such as sutures and intravenous catheters, are important predisposing factors to infection by Sta. aureus.
Several important toxins and enzymes are produced by Sta. aureus. The three clinically important exotoxins are enterotoxin, toxic shock syndrome toxin, and exfoliatin.
(1)
Enterotoxin
causes
food poisoning
characterized by prominent vomiting and watery, nonbloody diarrhea. It acts as a
superantigen
within the gastrointestinal tract to stimulate the release of large amounts of IL-1 and IL-2 from macrophages and helper T cells, respectively. The prominent vomiting appears to be caused by cytokines released from the lymphoid cells, which stimulate the enteric nervous system to activate the vomiting center in the brain.
(2)
Toxic shock syndrome toxin
(TSST) causes toxic shock, especially in
tampon-using
menstruating women or in individuals with
wound infections
. Toxic shock also occurs in patients with
nasal packing
used to stop bleeding from the nose. TSST is produced locally by Sta. aureus in the vagina, nose, or other infected site. The toxin enters the bloodstream, causing a
toxemia
. Blood cultures typically do not grow Sta. aureus.
TSST is a
superantigen
and causes toxic shock by stimulating the release of large amounts of IL-1, IL-2, and TNF. Approximately 5% to 25% of isolates of Sta. aureus carry the gene for TSST. Toxic shock occurs in people who do not have antibody against TSST.
(3)
Exfoliatin
causes
“scalded skin”
syndrome in young children. It is “epidermolytic” and acts as a protease that cleaves desmoglein in desmosomes, leading to the separation of the epidermis at the granular cell layer.
(4) Several exotoxins can kill leukocytes (leukocidins) and cause necrosis of tissues in vivo. Of these, the two most important are
alpha toxin
and
P-V leukocidin
.
(5) The enzymes include
coagulase, fibrinolysin, hyaluronidase, proteases, nucleases,

and
lipases
. Coagulase, by clotting plasma, serves to wall off the infected site, thereby retarding the migration of neutrophils into the site.

Staphylokinase is a fibrinolysin that can lyse thrombi.
P-V leukocidin
is a
pore-forming toxin
that kills cells, especially white blood cells, by damaging cell membranes. The two subunits of the toxin assemble in the cell membrane to form a pore through which cell contents leak out. The gene encoding P-V leukocidin is located on a lysogenic phage. The importance of P-V leukocidin as a virulence factor is indicated by the severe skin and soft tissue infection caused by
MRSA strains
that produce this leukocidin. A severe necrotizing pneumonia is also caused by strains of Sta. aureus that produce P-V leukocidin. Approximately 2% of clinical isolates of Sta. aureus produce P-V leukocidin.
Enterotoxin is fairly
heat-resistant
and is therefore usually not inactivated by brief cooking. It is
resistant to stomach acid
and to enzymes in the stomach and jejunum. There are six immunologic types of enterotoxin, types A–F.
Alpha toxin
causes marked
necrosis
of the skin and hemolysis. The cytotoxic effect of alpha toxin is attributed to the formation of
holes
in the cell membrane and the consequent loss of low-molecular-weight substances from the damaged cell.
Clinical Findings
The important clinical manifestations caused by Sta. aureus can be divided into two groups:
pyogenic
(pus-producing) and
toxin-mediated
. Sta. aureus is a major cause of skin, soft tissue, bone, joint, lung, heart, and kidney infections.
Pyogenic
Diseases
(1)
Skin infections
are very common. These include impetigo , furuncles, carbuncles , paronychia, cellulitis, folliculitis , hydradenitis suppurativa, conjunctivitis, eyelid infections (blepharitis and hordeolum), and postpartum breast infections (mastitis). Lymphangitis can occur, especially on the forearm associated with an infection on the hand.
(2)
Septicemia (sepsis)
can originate from any localized lesion, especially wound infection, or as a result of intravenous drug abuse. Sepsis caused by Sta. aureus has clinical features similar to those of sepsis caused by certain gram-negative bacteria, such as
Neisseria meningitidis
.
(3)
Endocarditis
may occur on normal or prosthetic heart valves, especially right-sided endocarditis (tricuspid valve) in intravenous drug users. (Prosthetic valve endocarditis is often caused by Sta. epidermidis.)
(4)
Osteomyelitis and arthritis
may arise either by hematogenous spread from a distant infected focus or be introduced locally at a wound site. Sta. aureus is a very common cause of these diseases, especially in children.
(5)
Postsurgical wound infections
are an important cause of morbidity and mortality in hospitals. Sta. aureus is the most common cause.
(6)
Pneumonia
can occur in postoperative patients or following viral respiratory infection, especially influenza. Staphylococcal pneumonia often leads to
empyema or lung abscess
. In many hospitals it is the most common cause of nosocomial pneumonia in general and especially of
ventilator-associated
pneumonia in intensive care units. CA-MRSA causes a severe
necrotizing pneumonia
.
(7)
Conjunctivitis
typically presents with unilateral burning eye pain, hyperemia of the conjunctiva, and a purulent discharge. The organism is transmitted to the eye by contaminated fingers. Sta. aureus is the most common cause overall, but
Streptococcus pneumoniae
and
Haemophilus influenzae
are more common in
children
.
Gonococcal and nongonococcal
(caused by Chlamydia trachomatis ) conjunctivitis is acquired by
infants
during passage through the birth canal.
(8)
Abscesses
can occur in any organ when the organism circulates in the bloodstream (bacteremia). These abscesses are often called
“metastatic abscesses”
because they occur by the spread of bacteria from the original site.
Toxin-Mediated Diseases
(1)
Food poisoning
(gastroenteritis) is caused by ingestion of enterotoxin, which is preformed in foods and hence has a short incubation period
(1–8 hours)
. In staphylococcal food poisoning, vomiting is typically more prominent than diarrhea.
(2)
Toxic shock syndrome
is characterized by
fever
;
hypotension
;

a diffuse, macular, sunburn-like

rash
that goes on to desquamate; and involvement of three or more of the following organs: liver, kidney, gastrointestinal tract, central nervous system, muscle, or blood.
(3)
Scalded-skin syndrome
is characterized by fever, large bullae, and an erythematous macular rash. Large areas of skin slough, serous fluid exudes, and electrolyte imbalance can occur. Hair and nails can be lost. Recovery usually occurs within 7–10 days. This syndrome occurs most often in
young children
.
Kawasaki
Syndrome
Kawasaki syndrome (KS) is a disease of unknown etiology that is discussed here because several of its features
resemble toxic shock syndrome
caused by the superantigens of Sta. aureus (and Str. pyogenes ). KS is a
vasculitis
involving small and medium-size arteries, especially the coronary arteries.
Staphylococcus saprophyticus
Staphylococcus epidermidis
Staphylococcus epidermidis is a coagulase-negative staphylococcus which can cause
endocarditis
and
prosthetic joint infections
.

It does not ferment mannitol or synthesize any pigments and produces white colonies. The virulence of Sta. epidermidis is significantly less than that of Sta. aureus.
Transmission
Sta. epidermidis is found primarily on the human
skin
and can enter the bloodstream at the site of intravenous catheters that penetrate through the skin.
Unlike Sta. aureus, coagulase-negative staphylococci do not produce exotoxins. Thus, Sta. epidermidis does not cause food poisoning or toxic shock syndrome. It do, however, cause
pyogenic infections
. For example, Sta. epidermidis is a prominent cause of pyogenic infections on prosthetic implants such as
heart valves and hip joints.
Pathogenesis
Sta. epidermidis infections are almost always hospital-acquired.
Clinical
Findings

Sta. epidermidis is part of the normal human flora on the skin and mucous membranes but can enter the bloodstream (bacteremia) and cause
metastatic infections
, especially at the site of implants. It commonly infects intravenous catheters and prosthetic implants (e.g., prosthetic heart valves [endocarditis], vascular grafts, and prosthetic joints [arthritis or osteomyelitis]).
Sta. epidermidis is also a major cause of
sepsis in neonates
and of

peritonitis in patients with renal failure
who are undergoing peritoneal dialysis through an indwelling catheter. It is the most common bacterium to cause
cerebrospinal fluid shunt infections.
Strains of Sta. epidermidis that produce a
glycocalyx
are more likely to adhere to prosthetic implant materials and therefore are more likely to infect these implants than strains that do not produce a glycocalyx. Hospital personnel are a major reservoir for antibiotic-resistant strains of Sta. epidermidis.
Staphylococcus saprophyticus is another coagulase-negative staphylococcus which causes
urinary tract infections
.
Transmission
Sta. saprophyticus is found primarily on the mucosa of the genital tract in
young women
and from that site can ascend into the urinary bladder to cause urinary tract infections.
Pathogenesis
Like Sta. epidermidis, It does not produce exotoxins, but cause
pyogenic infections
. Sta. saprophyticus causes urinary tract infections, especially cystitis.
Clinical Findings
In contrast to Sta. epidermidis, Sta. saprophyticus infections are almost always
community-acquired.
Sta. saprophyticus causes urinary tract infections, particularly in sexually active young women. Most women with this infection have had sexual intercourse within the previous 24 hours. This organism is second to
Escherichia coli
as a cause of community-acquired urinary tract infections in young women.
Laboratory Diagnosis
Smears
from staphylococcal lesions reveal gram-positive cocci in
grapelike clusters
. Cultures of Sta. aureus typically yield
golden-yellow colonies
that are usually
B-hemolytic
. Sta. aureus is coagulase-positive.
Mannitol-salt agar
is a commonly used screening device for Sta. aureus.
Cultures of coagulase-negative
staphylococci typically yield
white colonies
that are nonhemolytic. The two coagulase-negative staphylococci are distinguished by their reaction to the antibiotic
novobiocin
: Sta. epidermidis is sensitive, whereas Sta. saprophyticus is resistant. There are no serologic or skin tests used for the diagnosis of any acute staphylococcal infection.
In toxic shock syndrome, isolation of Sta. aureus is not required to make a diagnosis as long as the clinical criteria are met. Laboratory findings that support a diagnosis of toxic shock syndrome include the isolation of a TSST producing strain of Sta. aureus and development of antibodies to the toxin during convalescence, although the latter is not useful for diagnosis during the acute disease.
For epidemiological purposes, Sta. aureus can be subdivided into subgroups based on the susceptibility of the clinical isolate to lysis by a variety of bacteriophages. A person carrying Sta. aureus of the same phage group as that which caused the outbreak may be the source of the infections.
The type, location and severity of your infection all help determine which antibiotic is best. Other factors that come into play when choosing a Staph antibiotic are: pregnancy, drug allergies, other medications being taken and other health risks. The most accurate way to prescribe an antibiotic is to get tested to identify the best antibiotic that will work against the patient's particular infection.
Commonly prescribed Staph infection antibiotics can include (but are not limited to):
B-lactams: Such as Oxacillin, Flucloxacillin.
First generation Cephalosporins: Such as Cefazolin, Cephalothin and Cephalexin.
Lincosamides: Such as Clindamycin and Lincomycin.
Macrolides: Such as Erythromycin.
Tetracyclines: Such as Doxycycline, Minocycline.
Sulfa drugs.
Mupirocin cream (for nose infections).
Vancomycin (IV) and Linezolid (for severe or resistant MRSA strains).
Most of the above antibiotics are for less severe Staph infections. MRSA is resistant to the B-lactams listed above.
To Keep For Pharmacology Class
Resistance..
More than 90% of Sta. aureus strains contain plasmids that encode β-lactamase, the enzyme that degrades many, but not all, penicillins. Some strains of Sta. aureus are resistant to the β-lactamase–resistant penicillins, such as methicillin and nafcillin, by virtue of changes in the penicillinbinding protein (PBP) in their cell membrane. Genes on the bacterial chromosome called mecA genes encode these altered PBPs.
These strains are commonly known as methicillinresistant Sta. aureus (MRSA) or nafcillin-resistant Sta. aureus (NRSA). MRSA currently accounts for more than 50% of Sta. aureus strains isolated from hospital patients in the United States. The most common strain of MRSA in the United States is the “USA300” strain.
Strains of Sta. aureus with intermediate resistance to vancomycin (VISA) and with full resistance to vancomycin (VRSA) have also been detected. The cassette of genes that encodes vancomycin resistance in Sta. aureus is the same as the cassette that provides vancomycin resistance in enterococci. These genes are located in a transposon on a plasmid and encode the enzymes that substitute d -lactate for d -alanine in the peptidoglycan.
Prevention
There is
no vaccine
against staphylococci. Cleanliness, frequent handwashing, and aseptic management of lesions help to control spread of Sta. aureus. Persistent colonization of the nose by Sta. aureus can be reduced by intranasal mupirocin or by oral antibiotics, but is difficult to eliminate completely. Shedders may have to be removed from high-risk areas (e.g., operating rooms and newborn nurseries). Cefazolin is often used perioperatively to prevent staphylococcal surgical-wound infections.
Streptococci are
spherical
gram-positive cocci arranged in
chains
or
pairs
. All streptococci are
catalase-negative
, whereas staphylococci are catalase-positive.
Important Properties
Species of Streptococcus are classified based on their
hemolytic properties
.
Alpha-hemolytic
species cause oxidization of iron in hemoglobin molecules within red blood cells, giving it a greenish color on blood agar.
Beta-hemolytic
species cause complete rupture of red blood cells. On blood agar, this appears as wide areas clear of blood cells surrounding bacterial colonies.
Gamma-hemolytic
species cause no hemolysis.
Beta-hemolytic
streptococci are further classified by
Lancefield grouping
, a serotype classification (that is, describing specific carbohydrates present on the bacterial cell wall). The 20 described serotypes are named Lancefield groups
A to U
.
B-Hemolysis is due to the production of enzymes (hemolysins) called
streptolysin O
and
streptolysin S

Classification
many bacteria formerly considered Streptococcus were separated out into the genera
Enterococcus
and
Lactococcus
. Currently, over 50 species are recognised in this genus.

In the medical setting, the most important groups are the alpha-hemolytic streptococci
S. pneumoniae
and
Streptococcus viridans
group, and the beta-hemolytic streptococci of Lancefield groups A and B (also known as
“group A strep”
and
“group B strep”
).
There are two important antigens of B-hemolytic streptococci:

(1)
C carbohydrate
determines the group of B-hemolytic streptococci. It is located in the cell wall, and its specificity is determined by an amino sugar.

(2)
M protein
is the most important virulence factor and determines the type of group A B-hemolytic streptococci. It protrudes from the outer surface of the cell and interferes with ingestion by phagocytes (i.e., it is
antiphagocytic
). Antibody to M protein provides
type-specific immunity
.
There are approximately
80 serotypes
based on the
M protein
, which explains why multiple infections with
Str. Pyogenes
can occur. Strains of
Str. pyogenes
that produce certain M protein types are
rheumatogenic
(i.e., cause primarily rheumatic fever), whereas strains of
Str. Pyogenes
that produce other M protein types are
nephritogenic
(i.e., cause primarily acute glomerulonephritis). Although M protein is the main antiphagocytic component of
Str. pyogenes
, the organism also has a
polysaccharide capsule
that plays a role in retarding phagocytosis.
Classification of Streptococci
B-Hemolytic Streptococci
These are arranged into groups A–U (known as Lancefield groups) on the basis of antigenic differences in
C carbohydrate
. In the clinical laboratory, the group is determined by
precipitin tests
with specific antisera or by immunofluorescence.
Group A streptococci
(
Str. pyogenes
) are one of the most important human pathogens. They are the most frequent bacterial cause of
pharyngitis
and a very common cause of
skin infections
. They adhere to pharyngeal epithelium via pili composed of lipoteichoic acid and M protein. Many strains have a hyaluronic acid capsule that is antiphagocytic. The growth of
Str. pyogenes
on agar plates in the laboratory is
inhibited by the antibiotic bacitracin
, an important diagnostic criterion.
Group B streptococci
(
Str. agalactiae
) colonize the genital tract of some women and can cause
neonatal meningitis and sepsis
. They are usually
bacitracin-resistant
. They hydrolyze (break down)
hippurate
, an important diagnostic criterion.
Group D streptococci
include
enterococci
(e.g.,
Ent. faecalis

and

Enterococcus faecium
) and
nonenterococci
(e.g.,
Str. bovis
). Enterococci are members of the normal flora of the colon and are noted for their ability to cause urinary, biliary, and cardiovascular infections. They are very hardy organisms; they
can grow in hypertonic (6.5%) saline or in bile and are not killed by penicillin G
. As a result, a synergistic combination of penicillin and an aminoglycoside (e.g., gentamicin) is required to kill enterococci.
Nonenterococcal
group D streptococci, such as
Str.bovis
, can cause similar infections but are much
less hardy
organisms (e.g., they are inhibited by 6.5% NaCl and killed by penicillin G). Note that the hemolytic reaction of group D streptococci is variable:
most are a-hemolytic
, but some are B-hemolytic, and others are nonhemolytic. Groups C, E, F, G, H, and K–U streptococci infrequently cause human disease.
Non–B-Hemolytic Streptococci
Some produce
no hemolysis
; others produce
a-hemolysis
. The principal a-hemolytic organisms are
Str. Pneumoniae
(pneumococci) and the
viridans group
of streptococci (e.g., Streptococcus mitis, Streptococcus sanguis, and Streptococcus mutans).
Viridans streptococci
are part of the normal flora of the human
pharynx
and intermittently reach the bloodstream to cause
infective endocarditis
.
Str. mutans
synthesizes polysaccharides (dextrans) that are found in dental plaque and lead to
dental caries
. Streptococcus intermedius and Streptococcus anginosus (also known as the Str. Anginosusmilleri group) are usually a-hemolytic or nonhemolytic, but some isolates are B-hemolytic. They are found primarily in the mouth and colon.
Peptostreptococci
These grow under
anaerobic or microaerophilic conditions
and produce
variable hemolysis
. Peptostreptococci are members of the normal flora of the gut, mouth, and the female genital tract and participate in mixed anaerobic infections.
Transmission
Most streptococci are part of the normal flora of the human throat, skin, and intestines but produce disease when they gain access to tissues or blood. Viridans streptococci and Str. pneumoniae are found chiefly in the oropharynx; Str. pyogenes is found on the skin and in the oropharynx in small numbers; Str. agalactiae occurs in the vagina and colon; and both the enterococci and anaerobic streptococci are located in the colon.
Pathogenesis
Group A streptococci ( Str. pyogenes ) cause disease by three mechanisms:

(1)
pyogenic inflammation
, which is induced locally at the site of the organisms in tissue;

(2)
exotoxin production
, which can cause widespread systemic symptoms in areas of the body where there are no organisms;

(3)
immunologic
, which occurs when antibody against a component of the organism cross-reacts with normal tissue or forms immune complexes that damage normal tissue. The immunologic reactions cause inflammation (e.g., the inflamed joints of rheumatic fever), but there are no organisms in the lesions
The
M protein
of Str. pyogenes is its most important antiphagocytic factor, but its
capsule
, composed of hyaluronic acid, is also antiphagocytic. Antibodies are not formed against the capsule because hyaluronic acid is a normal component of the body and humans are tolerant to it.
Group
A
streptococci produce three important inflammation- related enzymes:
In additon, group
A
streptococci produce five importanttoxins and hemolysins:
(1)
Hyaluronidase
degrades hyaluronic acid, which is the ground substance of subcutaneous tissue. Hyaluronidase is known as
spreading factor
because it facilitates the rapid spread of
Str. pyogenes
in skin infections (
cellulitis
).
(2)
Streptokinase
(fibrinolysin) activates plasminogen to form plasmin, which dissolves fibrin in clots, thrombi, and emboli. It can be used to
lyse thrombi
in the coronary arteries of heart attack patients.
(3)

DNase
(streptodornase) degrades DNA in exudates or necrotic tissue. Antibody to DNase B develops during pyoderma; this can be used
for diagnostic purposes
. Streptokinase–streptodornase mixtures applied as a skin test give a positive reaction in most adults, indicating normal cell-mediated immunity.
(1)
Erythrogenic toxin

causes the
rash
of scarlet fever. Its mechanism of action is similar to that of the toxic shock syndrome toxin (TSST) of
Sta. aureus
(i.e., it acts as a superantigen). It is produced only by certain strains of
Str. pyogenes
lysogenized by a bacteriophage carrying the gene for the toxin. The injection of a skin test dose of erythrogenic toxin (
Dick test
) gives a positive result in persons lacking antitoxin (i.e., susceptible persons).
(2)
Streptolysin O
is a hemolysin that is inactivated by oxidation (
oxygen-labile
). It causes B-hemolysis only when colonies grow under the surface of a blood agar plate. It is antigenic, and antibody to it (
ASO
) develops after group A streptococcal infections. The titer of ASO antibody can be important in the diagnosis of
rheumatic fever
.
(3)
Streptolysin S
is a hemolysin that is not inactivated by oxygen (
oxygen-stable
). It is not antigenic but is responsible for B-hemolysis when colonies grow on the surface of a blood agar plate.
(4)
Pyrogenic exotoxin

A
is the toxin responsible for most cases of
streptococcal toxic shock syndrome
. It has the same mode of action as does staphylococcal TSST (i.e., it is a
superantigen
that causes the release of large amounts of cytokines from helper T cells and macrophages).
(5)
Exotoxin B
is a protease that rapidly destroys tissue and is produced in large amounts by the strains of
Str. pyogenes
, the so-called
“flesh-eating”
streptococci that cause
necrotizing fasciitis
.
Pathogenesis by group B streptococci (
Str. agalactiae
) is based on the ability of the organism to induce an
inflammatory response
. However, unlike
Str. pyogenes
,
no cytotoxic enzymes or exotoxins
have been described, and there is no evidence for any immunologically induced disease. Group B streptococci have a
polysaccharide capsule
that is antiphagocytic and anticapsular antibody is
protective
.
Group B Streptococci
Pathogenesis by
Str. pneumoniae
and the
viridans streptococci
is uncertain, as no exotoxins or tissue-destructive enzymes have been demonstrated. The main virulence factor of
Str. pneumoniae
is its
antiphagocytic polysaccharide capsule
. Many of the strains of viridans streptococci that cause endocarditis produce a
glycocalyx
that enables the organism to adhere to the heart valve.
Clinical Findings
Str. pyogenes
Str. pyogenes (group A streptococcus) is the most common bacterial cause of
pharyngitis
(sore throat). Streptococcal pharyngitis (strep throat) is characterized by throat pain and fever. On examination, an inflamed throat and tonsils, often with a yellowish exudate, are found, accompanied by tender cervical lymph nodes.
If the infecting streptococci produce
erythrogenic toxin
and the host lacks antitoxin,
scarlet fever
may result. A
“strawberry” tongue
is a characteristic lesion seen in scarlet fever. Str. pyogenes also causes another toxin-mediated disease, streptococcal toxic shock syndrome, which has clinical findings similar to those of staphylococcal toxic shock syndrome. However, streptococcal TSS typically has a recognizable site of pyogenic inflammation and blood cultures are often positive, whereas staphylococcal TSS typically has neither a site of pyogenic inflammation nor positive blood cultures.
Str. pyogenes causes three types of diseases:

(1)
pyogenic diseases
such as pharyngitis and cellulitis,

(2)
toxigenic diseases
such as scarlet fever and toxic shock syndrome,

(3)
immunologic diseases
such as rheumatic fever and acute glomerulonephritis (AGN).
If untreated, spontaneous recovery often occurs in 10 days, but rheumatic fever may occur. Untreated pharyngitis may extend to the middle ear (otitis media), the sinuses (sinusitis), the mastoids (mastoiditis), or the meninges (meningitis). Continuing inability to swallow may indicate a peritonsillar or retropharyngeal abscess.
Group A streptococci
Group A streptococci cause skin and soft tissue infections, such as cellulitis, erysipelas, necrotizing fasciitis (streptococcal gangrene), and impetigo. Impetigo, a form of pyoderma, is a superficial skin infection characterized by “honey-colored” crusted lesions. Lymphangitis can occur, especially on the forearm associated with an infection on the hand.
Group A streptococci also cause endometritis (puerperal fever), a serious infection of pregnant women, and sepsis. Immune-mediated poststreptococcal AGN can also occur, especially following skin infections caused by certain M protein types of Str. pyogenes .
Group B streptococci
Group B streptococci cause
neonatal sepsis
and
meningitis
. The main predisposing factor is prolonged (longer than 18 hours) rupture of the membranes in women who are colonized with the organism. Children born prior to 37 weeks’ gestation have a greatly increased risk of disease.

Also, children whose mothers lack antibody to group B streptococci and who consequently are born without transplacentally acquired IgG have a high rate of neonatal sepsis caused by this organism. Group B streptococci are an important cause of neonatal pneumonia as well.
Although most group B streptococcal infections are in neonates, this organism also causes such infections as pneumonia, endocarditis, arthritis, cellulitis, and osteomyelitis in adults. Postpartum endometritis also occurs. Diabetes is the main predisposing factor for adult group B streptococcal infections.
Viridans streptococci (e.g., Str. mutans, Str. sanguis, Str. salivarius, and Str. mitis ) are the most common cause of
infective endocarditis
. They enter the bloodstream (bacteremia) from the oropharynx, typically after
dental surgery
.
Signs of endocarditis are fever, heart murmur, anemia, and embolic events such as
splinter hemorrhages
,
subconjunctival petechial hemorrhages
, and
Janeway lesions
. The heart murmur is caused by vegetations on the heart valve. It is 100% fatal unless effectively treated with antimicrobial agents. About 10% of endocarditis cases are caused by enterococci, but any organism causing bacteremia may settle on deformed valves. At least three blood cultures are necessary to ensure recovery of the organism in more than 90% of cases.
Viridans streptococci, especially Str. anginosus, Str. milleri, and Str. intermedius, also cause brain abscesses, often in combination with mouth anaerobes (a
mixed aerobic– anaerobic infection
).

Dental surgery
is an important predisposing factor to brain abscess because it provides a portal for the viridans streptococci and the anaerobes in the mouth to enter the bloodstream (bacteremia) and spread to the brain. Viridans streptococci are involved in mixed aerobic–anaerobic infections in other areas of the body as well (e.g., abdominal abscesses).
Viridans streptococci
Enterococci cause
urinary tract infections
, especially in hospitalized patients. Indwelling urinary catheters and urinary tract instrumentation are important predisposing factors.
Enterococci also cause
endocarditis
, particularly in patients who have undergone gastrointestinal or urinary tract surgery or instrumentation. They also cause intra-abdominal and pelvic infections, typically in combination with anaerobes.
Str. bovis, a nonenterococcal group D streptococcus, causes endocarditis, especially in patients with carcinoma of the colon. This association is so strong that patients with Str. bovis, bacteremia or endocarditis should be investigated for the presence of colonic carcinoma.
Group D Streptococci
Poststreptococcal (Nonsuppurative)Diseases
Peptostreptococci are one of the most common bacteria found in brain, lung, abdominal, and pelvic abscesses.
These are disorders in which a local infection with group A streptococci is followed weeks later by inflammation in an organ that was not infected by the streptococci. The inflammation is caused by an
immunologic (antibody) response
to streptococcal M proteins that cross-react with human tissues.
Some strains of Str. pyogenes bearing certain M proteins are nephritogenic and cause AGN, and other strains bearing different M proteins are rheumatogenic and cause acute rheumatic fever. Note that these diseases appear several weeks after the actual infection because that's the length of time it takes to produce sufficient antibodies.
Acute Glomerulonephritis
Acute
Rheumatic Fever
AGN typically occurs 2 to 3 weeks after skin infection by certain group A streptococcal types in children (e.g., M protein type 49 causes AGN most frequently). AGN is more frequent after skin infections than after pharyngitis. The most striking clinical features are hypertension, edema of the face (especially periorbital edema) and ankles, and “smoky” urine (due to red cells in the urine). Most patients recover completely. Reinfection with streptococci rarely leads to recurrence of glomerulonephritis.
The disease is initiated by
antigen–antibody complexes on the glomerular basement membrane
, and soluble antigens from streptococcal membranes may be the inciting antigen. It can be prevented by early eradication of nephritogenic streptococci from skin colonization sites but not by administration of penicillin after the onset of symptoms.
Approximately 2 weeks after a group A streptococcal infection—usually pharyngitis—rheumatic fever, characterized by fever, migratory polyarthritis, and carditis, may develop. The carditis damages myocardial and endocardial tissue, especially the mitral and aortic valves, resulting in vegetations on the valves. Uncontrollable, spasmodic movements of the limbs or face (chorea) may also occur. ASO titers and the erythrocyte sedimentation rate are elevated.
Note that group A streptococcal skin infections do not cause rheumatic fever. Most cases of pharyngitis caused by group A streptococci occur in children aged 5 to 15 years, and hence rheumatic fever occurs in that age group.
Rheumatic fever is due to an
immunologic reaction between cross-reacting antibodies to certain streptococcal M proteins and antigens of joint, heart, and brain tissue
. It is an autoimmune disease, greatly exacerbated by recurrence of streptococcal infections. If streptococcal infections are treated within 8 days of onset, rheumatic fever is usually prevented.

After a heart-damaging attack of rheumatic fever, reinfection must be prevented by long-term prophylaxis. In the United States, fewer than 0.5% of group A streptococcal infections lead to rheumatic fever, but in developing tropical countries, the rate is higher than 5%.
Diagnosis
Microbiologic
Serologic
ASO titers
are high soon after group A streptococcal infections. In patients suspected of having
rheumatic fever
, an elevated ASO titer is typically used as evidence of previous infection because throat culture results are often
negative
at the time the patient presents with rheumatic fever. Titers of
anti-DNase B
are high in group A streptococcal skin infections and serve as an indicator of previous streptococcal infection in patients suspected of having
AGN
.
Gram-stained smears
are useless in streptococcal pharyngitis because viridans streptococci are members of the normal flora and cannot be visually distinguished from the pathogenic Str. pyogenes. However, stained smears from skin lesions or wounds that reveal streptococci are diagnostic.

Cultures
of swabs from the pharynx or lesion on blood agar plates show small, translucent B-hemolytic colonies in 18 to 48 hours. If inhibited by bacitracin disk, they are likely to be group A streptococci.
Group B streptococci are characterized by their ability to hydrolyze hippurate and by the production of a protein that causes enhanced hemolysis on sheep blood agar when combined with B-hemolysin of Sta. aureus (
CAMP test
). Group D streptococci hydrolyze esculin in the presence of bile (i.e., they produce a
black pigment on bile-esculin agar
). The group D organisms are further subdivided: the enterococci grow in hypertonic (6.5%) NaCl, whereas the nonenterococci do not.
Although
cultures
remain the
gold standard
for the diagnosis of streptococcal pharyngitis, a problem exists because the results of culturing are not available for at least
18 hours
, and it is beneficial to know while the patient is in the office whether antibiotics should be prescribed. For this reason, rapid tests that provide a diagnosis in approximately 10 minutes were developed.
The rapid test detects
bacterial antigens
in a throat swab specimen. In the test, specific antigens from the group A streptococci are extracted from the throat swab with certain enzymes and are reacted with antibody to these antigens bound to latex particles.
Agglutination
of the
colored latex particles
occurs if group A streptococci are present in the throat swab. The specificity of these tests is high but the sensitivity is low (i.e., false-negative results can occur). If the test result is negative but the clinical suspicion of streptococcal pharyngitis is high, a culture should be done.
A rapid test is also available for the detection of group B streptococci in vaginal and rectal samples. It
detects the DNA
of the organism, and results can be obtained in approximately 1 hour. Viridans group streptococci form a-hemolytic colonies on blood agar and must be distinguished from Str. Pneumoniae (pneumococci), which is also a-hemolytic. Viridans group streptococci are resistant to lysis by bile and will grow in the presence of
optochin
, whereas pneumococci will not. The various viridans group streptococci are classified into species by using a variety of biochemical tests.
Treatment
Group A streptococcal infections can be treated with either penicillin G or amoxicillin, but neither rheumatic fever nor AGN patients benefit from penicillin treatment after the onset of the two diseases.

Endocarditis caused by most viridans streptococci is curable by prolonged penicillin treatment. However, enterococcal endocarditis can be eradicated only by a penicillin or vancomycin combined with an aminoglycoside.

VREs are now an important cause of nosocomial infections; there is no reliable antibiotic therapy for these organisms.

Nonenterococcal group D streptococci (e.g., Str. bovis ) are not highly resistant and can be treated with penicillin G.

The drug of choice for group B streptococcal infections is either penicillin G or ampicillin.
Prevention
Rheumatic fever can be prevented by prompt treatment of group A streptococcal pharyngitis with penicillin. Prevention of streptococcal infections (usually with benzathine penicillin once each month for several years) in persons who have had rheumatic fever is important to prevent recurrence of the disease. There is no evidence that patients who have had AGN require similar penicillin prophylaxis.
In patients with damaged heart valves who undergo invasive dental procedures, endocarditis caused by viridans streptococci can be prevented by using amoxicillin perioperatively. To avoid unnecessary use of antibiotics, it is recommended to give amoxicillin prophylaxis only to those patients who have the highest risk of severe consequences from endocarditis and who are undergoing the highest risk dental procedures. It is no longer recommended that patients undergoing GI or GU tract procedures receive prophylaxis.
The incidence of neonatal sepsis caused by group B streptococci can be reduced by a two-pronged approach:
(1) Pregnant women screening (at 35 to 37 weeks' gestation).

(2) Intravenous penicillin G (or ampicillin) administration at the time of delivery to women who experience prolonged (longer than 18 hours) rupture of membranes, whose labor begins before 37 weeks' gestation, or who have a fever at the time of labor.
There are no vaccines available against any of the streptococci except Str. pneumoniae
Streptococcus
Pneumonia
Streptococcus pneumoniae causes pneumonia, bacteremia, meningitis, and infections of the upper respiratory tract such as otitis media, mastoiditis, and sinusitis. Pneumococci are the most common cause of community-acquired pneumonia, meningitis, sepsis in splenectomized individuals, otitis media, and sinusitis. They are a common cause of conjunctivitis, especially in children. Note that Str. Pneumoniae is also known as the pneumococcus (plural, pneumococci).
Important
Properties
Pneumococci are gram-positive lancet-shaped cocci arranged in pairs (
diplococci
) or short chains. (The term lancet-shaped means that the diplococci are oval with somewhat pointed ends rather than being round.) On blood agar they produce a-hemolysis. In contrast to viridans streptococci, they are lysed by bile or deoxycholate, and their growth is inhibited by optochin.
Pneumococci possess
polysaccharide capsules
of more than 85 antigenically distinct types. With type-specific antiserum, capsules swell (
quellung reaction
), and this can be used to identify the type. Capsules are virulence factors (i.e., they interfere with phagocytosis and favor invasiveness). Specific antibody to the capsule opsonizes the organism, facilitates phagocytosis, and promotes resistance. Such antibody develops in humans as a result either of infection (asymptomatic or clinical) or of administration of polysac-charide vaccine. Capsular polysaccharide elicits primarily a B-cell (i.e., T-independent) response.
Another important surface component of Str. Pneumoniae is a teichoic acid in the cell wall called
C-substance
(also known as
C-polysaccharide
). It is medically important not for itself, but because it reacts with a normal serum protein made by the liver called
C-reactive protein
(CRP).
CRP is an “acute-phase” protein that is elevated as much as 1000-fold in acute inflammation.
CRP is not an antibody (which are B-globulins) but rather a B-globulin. (Plasma contains a-, B-, and ةة-globulins.) Note that CRP is a nonspecific indicator of inflammation and is elevated in response to the presence of many organisms, not just Str. pneumoniae. Clinically, CRP in human serum is measured in the laboratory by its reaction with the carbohydrate of Str. pneumoniae. The medical importance of CRP is that an elevated CRP appears to be a better predictor of heart attack risk than an elevated cholesterol level.
y
Transmission
Humans are the natural hosts for pneumococci; there is no animal reservoir. Because a proportion (5%–50%) of the healthy population harbor virulent organisms in the oropharynx, pneumococcal infections are not considered to be communicable. Resistance is high in healthy young people, and disease results most often when predisposing factors are present.
Pathogenesis
The most important virulence factor is the capsular polysaccharide, and anticapsular antibody is protective.
Lipoteichoic acid, which activates complement and induces inflammatory cytokine production, contributes to the inflammatory response and to the septic shock syndrome that occurs in some immunocompromised patients. Pneumolysin, the hemolysin that causes a-hemolysis, may also contribute to pathogenesis.
Pneumococci produce IgA protease that enhances the organism’s ability to colonize the mucosa of the upper respiratory tract. Pneumococci multiply in tissues and cause inflammation. When they reach alveoli, there is outpouring of fluid and red and white blood cells, resulting in consolidation of the lung. During recovery, pneumococci are phagocytized, mononuclear cells ingest debris, and the consolidation resolves.
(1) alcohol or drug intoxication or other cerebral impairment that can depress the cough reflex and increase aspiration of secretions;
(2) abnormality of the respiratory tract (e.g., viral infections), pooling of mucus, bronchial obstruction, and respiratory tract injury caused by irritants (which disturb the integrity and movement of the mucociliary blanket);
(3) abnormal circulatory dynamics (e.g., pulmonary congestion and heart failure);
(4)
splenectomy
;
(5) certain chronic diseases such as sickle cell anemia and nephrosis.
Factors that lower resistance and predispose persons to pneumococcal infection include:
Patients with
sickle cell anemia
auto-infarct their spleen, become functionally asplenic, and are predisposed to pneumococcal sepsis. Trauma to the head that causes
leakage of spinal fluid
through the nose predisposes to pneumococcal meningitis.
Pneumonia often begins with a sudden chill, fever, cough, and pleuritic pain.
Sputum is a red or brown “rusty” color
. Bacteremia occurs in 15% to 25% of cases. Spontaneous recovery may begin in 5 to 10 days and is accompanied by development of anticapsular antibodies. Pneumococci are a prominent cause of otitis media, sinusitis, mastoiditis, conjunctivitis, purulent bronchitis, pericarditis, bacterial meningitis, and sepsis. Pneumococci are the leading cause ofsepsis in patients without a functional spleen.
Clinical Findings
Laboratory Diagnosis
In sputum, pneumococci are seen as
lancet-shaped
grampositive diplococci in Gram-stained smears.
They can also be detected by using the
quellung reaction
with multitype antiserum. On blood agar, pneumococci form small αa-hemolytic colonies. The colonies are bilesoluble (i.e., are lysed by bile), and growth is inhibited by optochin.
Blood cultures
are positive in 15% to 25% of pneumococcal infections.
Culture of cerebrospinal fluid
is usually positive in meningitis. Rapid diagnosis of pneumococcal meningitis can be made by detecting its capsular polysaccharide in spinal fluid using the latex agglutination test. A rapid test that detects urinary antigen (capsular polysaccharide) is also available for the diagnosis of pneumococcal pneumonia and bacteremia. Because of the increasing numbers of strains resistant to penicillin, antibiotic sensitivity tests must be done on organisms isolated from serious infections.
Treatment
Penicillins, erythromycin and fluoroquinolone can be used.
An increasing percentage of isolates, ranging from 15% to 35% depending on location, show high-level resistance.
Prevention
Despite the efficacy of antimicrobial drug treatment, the mortality rate is high in elderly (i.e., persons older than 65 years), immunocompromised (especially splenectomized), or debilitated persons. Such persons should be immunize with the polyvalent (23-type)
polysaccharide vaccine
. The vaccine is safe and fairly effective and provides long-lasting (at least 5 years) protection.
A booster dose is recommended for:
(1) people older than 65 years who received the vaccine more than 5 years ago and who were younger than 65 years when they received the vaccine, and
(2) people between the ages of 2 and 64 years who are asplenic, HIV-infected, receiving cancer chemotherapy, or receiving immunosuppressive drugs to prevent transplant rejection.
Oral penicillin is given to young children with hypogammaglobulinemia or splenectomy because such children are prone to pneumococcal infections and respond poorly to the vaccine.
A different pneumococcal vaccine containing pneumococcal
polysaccharide coupled (conjugated) to a carrier protein (diphtheria toxoid)
is given to children younger than 5 years. This “conjugate” vaccine is effective in young children in preventing both bacteremic infections, such as meningitis, and mucosal infections, such as otitis media. The vaccine containing the capsular polysaccharide of the seven most common pneumococcal serotypes has been replaced by a vaccine containing the 13 most common serotypes.
Immunization of
children
reduces the incidence of pneumococcal disease in
adults

because children are the main source of the organism for adults and immunization reduces the carrier rate in children.
(group A streptococcus) is the leading bacterial cause of pharyngitis and cellulitis. It is an important cause of impetigo, necrotizing fasciitis, and streptococcal toxic shock syndrome. It is also the inciting factor of two important immunologic diseases, namely, rheumatic fever and acute glomerulonephritis.
Streptococcus agalactiae (group B streptococcus) is the leading cause of neonatal sepsis and meningitis.
Enterococcus faecalis is an important cause of hospital-acquired urinary tract infections and endocarditis.
Viridans group streptococci are the most common cause of endocarditis. Streptococcus bovis also causes endocarditis.
Diseases
Pneumococci and viridans streptococci are distinguished in the clinical laboratory by two main criteria:
(1) the growth of
pneumococci
is
inhibited by

optochin
, whereas the growth of viridans streptococci is not inhibited; and

(2) colonies of pneumococci dissolve when exposed to bile (
bile-soluble
), whereas colonies of viridans streptococci do not dissolve.
The term
mixed anaerobic infections
refers to the fact that these infections are caused by multiple bacteria, some of which are
anaerobes
and others are
facultatives
. For example, peptostreptococci and viridans streptococci, both members of the oral flora, are often found in
brain abscesses
following dental surgery. Peptostreptococcus magnus and Peptostreptococcus anaerobius are the species frequently isolated from clinical specimens.
Esculin Test
Enterococcus faecalis
(ATCC ® 29212) colonies growing on Bile Esculin Agar with Azide (Cat. no. G11). Incubated aerobically for 24 hours at 35ºC.
Streptococcus pyogenes
(ATCC ® 19615) growth inhibited on Bile Esculin Agar with Azide (Cat. no. G11). Incubated aerobically for 24 hours at 35ºC.
To Sum Up
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Yasmeen Y. Sarraj
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