Bacterial pathogens and associated diseases- I.pdf

BACTERIAL PATHOGENS AND ASSOCIATED DISEASES
Nilufa Yeasmin, Associate Professor, College of Pharmaceutical Sciences, Mohuda Page 1
Staphylococcus
Structure and Physiology:
• Staphylococcus1 is a genus of Gram-positive, facultatively anaerobic prokaryotes whose spherical
cells are typically clustered in grapelike arrangements.
• This arrangement results from two characteristics of cell division: cell divisions occur in
successively different planes, and daughter cells remain attached to one another.
• Staphylococcal cells are 0.5–1.0 μm in diameter, nonmotile, and salt tolerant—they are capable of
growing in media that are up to 10% NaCl.
• Two species are commonly associated with staphylococcal diseases in humans:
• Staphylococcus aureus is the more virulent, producing a variety of disease conditions and
symptoms depending on the site of infection.
• Staphylococcus epidermidis, is a part of the normal microbiota of human skin, but it is an
opportunistic pathogen in immunocompromised patients or when introduced into the body
via intravenous catheters or on prosthetic devices, such as artificial heart valves.
Pathogenicity:
“Staph” infections result when staphylococci breach the body’s physical barriers (skin or mucous
membranes); entry of only a few hundred bacteria can ultimately result in disease.
The pathogenicity of Staphylococcus results from three features:
1. Structures that enable it to evade phagocytosis,
2. The production of enzymes,
3. The production of toxins.
Structural Defenses Against Phagocytosis
➢ The cells of S. aureus are uniformly coated with a protein, called protein A. By binding with the
antibody stems, effectively inhibits opsonization. Thereby inhibit phagocytosis.
Protein A also inhibits the complement cascade, which is triggered by antibody molecules bound to antigen.
➢ The outer surfaces of most pathogenic strains of S. Aureus also contain bound coagulase, an enzyme
that converts the soluble blood protein fibrinogen into long, insoluble fibrin molecules, which are
threads that form blood clots around the bacteria. Fibrin clots in effect hide the bacteria from
phagocytic cells.
➢ Both S. aureus and S. epidermidis also evade the body’s defences by synthesizing loosely
organized polysaccharide slime layers (sometimes called capsules) that inhibit chemotaxis of and
endocytosis by leukocytes, particularly neutrophils.
Enzymes

• Cell-free coagulase, like bound coagulase, triggers blood clotting.
• Hyaluronidase breaks down hyaluronic acid, which is a major component of the matrix between cells.
Hyaluronidase enables the bacteria to spread between cells throughout the body.
• Staphylokinase (produced by S. aureus) dissolves fibrin threads in blood clots, allowing S. aureus to free
itself from clots.
• Lipases digest lipids, allowing staphylococci to grow on the surface of the skin and in cutaneous oil
glands. All staphylococci produce lipases.
• β-lactamase (penicillinase), now present in over 90% of S. Aureus strains, breaks down penicillin. β-
lactamase allows the bacteria to survive treatment with beta-lactam antimicrobial drugs, such as penicillin
and cephalosporin.
Toxins
• Cytolytic toxins: So-called alpha, beta, gamma, and delta toxins are proteins, coded by chromosomal
genes, that disrupt the cytoplasmic membranes of a variety of cells, including leukocytes (white blood
cells). Leukocidin is a fifth cytolytic toxin that lyses leukocytes specifically, providing Staphylococcus with
some protection against phagocytosis.
• Exfoliative toxins cause the dissolution of epidermal desmosomes, causing the patient’s skin cells to
separate from each other and slough off the body.
• Toxic-shock syndrome (TSS) toxin: This protein causes toxicshock syndrome.
• Enterotoxins: These five proteins stimulate the intestinal muscle contractions, nausea, and intense
vomiting associated with staphylococcal food poisoning.
Epidemiology:
o Staphylococcus epidermidis is ubiquitous on human skin, whereas S. aureus is commonly found
only on moist skin folds.
o Both species also grow in the upper respiratory, gastrointestinal, and urogenital tracts of humans.
o Both bacteria are transmitted through direct contact between individuals as well as via fomites such
as contaminated clothing, bedsheets, and medical instruments.
Diseases:
Noninvasive Disease:
• Staphylococcus aureus is one of the more common causes of food poisoning.
• This is food intoxication because disease is caused by enterotoxin-contaminated food rather than by
invasion of bacteria.
• Commonly affected foods include processed meats, custard pastries, potato salad, and ice cream
that have been contaminated with bacteria from human skin.

• The food must remain at room temperature or warmer for several hours for the bacteria to grow,
reproduce, and secrete toxin.
• Warming or reheating inoculated food does not inactivate enterotoxins, which are heatstable,
although heating does kill the bacteria.
• Symptoms, which include nausea, severe vomiting, diarrhoea, headache, sweating, and abdominal
pain, usually appear within four hours following ingestion.
Cutaneous Diseases:
• Staphylococcal scalded skin syndrome is a reddening of the skin that typically begins near the
mouth, spreads over the entire body, and is followed by large blisters that contain clear fluid lacking
bacteria or white blood cells. Within two days the affected outer layer of skin (epidermis) peels off
in sheets, as if it had been dipped into boiling water.
• Small, flattened, red patches on the face and limbs, particularly of children whose immune systems
are not fully developed, characterize impetigo. The patches develop into pus-filled vesicles that
eventually crust over and the pus is filled with bacteria and white blood cells.
• Folliculitis is an infection of a hair follicle in which the base of the follicle becomes red, swollen,
and pus filled. When this condition occurs at the base of an eyelid, it is called a sty.
• A furuncle or boil is a large, painful, raised nodular extension of folliculitis into surrounding tissue.
• When several furuncles coalesce, they form a carbuncle, which extends deeper into the tissues,
triggering the fever and chills.
Systemic Diseases:
• Toxic-Shock Syndrome (Non-streptococcal): When strains of Staphylococcus that produce TSS
toxin grow in a wound, the toxin can be absorbed into the blood and cause toxic-shock syndrome,
non-streptococcal (TSS), characterized by fever, vomiting, red rash, extremely low blood pressure,
and loss of sheets of skin.
• Bacteremia: S. aureus is a common cause of bacteremia, the presence of bacteria in the blood.
After staphylococci enter the blood from a site of infection, they travel to other organs of the body,
which may become infected. Nosocomial (hospitalacquired) infections account for about half of all
cases of staphylococcal bacteremia.
• Endocarditis: S. aureus may attack the lining of the heart (including its valves), producing a
condition called endocarditis. Typically, patients with endocarditis have nonspecific, flulike
symptoms, but their condition quickly deteriorates as the amount of blood pumped from the heart
drops precipitously.
• Pneumonia and Empyema: Staphylococcus in the blood can invade the lungs, causing
pneumonia- an inflammation of the lungs in which the alveoli and bronchioles become filled with

fluid. In 10% of patients with staphylococcal pneumonia, this fluid is pus-a condition known as
empyema.
• Osteomyelitis: When Staphylococcus invades a bone, either through a traumatic wound or via the
blood during bacteremia, it causes osteomyelitis-inflammation of the bone marrow and the
surrounding bone. Osteomyelitis is characterized by pain in the infected bone accompanied by high
fever.
Diagnosis:
▪ Physicians diagnose staphylococcal infection by detecting grapelike arrangements of Gram-positive
bacteria isolated from pus, blood, or other fluids.
▪ If staphylococci isolated from an infection are able to clot blood, then they are coagulase positive
S. aureus.
Treatment:
▪ S. aureus is sensitive to benzyl penicillin, but about 90% strains found in hospital are now resistant.
▪ For this reason, the semisynthetic form of penicillin―methicillin, which is not inactivated by β-
lactamase became the drug of choice for staphylococcal infections.
▪ Unfortunately, methicillinresistant Staphylococcus aureus (MRSA) has emerged as a major
problem. MRSA is also resistant to many other common antimicrobial drugs, including penicillin,
macrolides, aminoglycosides, and cephalosporin; as a result, vancomycin has been used to treat
MRSA infections.
Prevention:
▪ It is imperative that health care workers take precautions against introducing the bacterium into
patients.
▪ Fortunately, because a large inoculums is required to establish an infection, proper cleansing of
wounds and surgical openings, attention to aseptic use of catheters and indwelling needles, and the
appropriate use of antiseptics will prevent infections in most healthy patients
▪ The most important measure for protecting against nosocomial infection is frequent hand washing.
▪ Scientists are currently testing the efficacy and safety of a vaccine that has proven effective in
protecting dialysis patients from S. aureus infections.
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Streptococcus:
The genus Streptococcus is a diverse assemblage of Gram-positive cocci 0.5–1.2 μm in diameter and
arranged in pairs or chains. They are catalase negative, although they do synthesize peroxidase and thus are
facultatively anaerobic. Streptococci do not produce spores and are non-motile.
Classification of streptococci based on phylogenetic group are:

• The pyogenic (pus generating) group includes most species that are overt human and animal pathogens.
• The mitis group includes commensals of the human oral cavity and pharynx, although one of the species,
Streptococcus pneumoniae, is also one of the most important human pathogens.
• The anginosus and salivarius groups are part of the commensal microbiota of the oral cavity and
pharynx.
• The bovis group belongs in the colon.
• The mutans group of streptococci colonizes exclusively the tooth surfaces of man and some animals;
some species belonging to this cluster are involved in the development of dental caries.
Depending on the haemolytic activity, streptococci are classified as-
• α-haemolysis streptococci
• β- haemolysis streptococci
• γ- haemolysis streptococci
Lancefield grouping- Rebecca Lancefield divides streptococci into serotype groups based on the bacteria’s
antigens (known, appropriately, as Lancefield antigens). The serotypes in this scheme include
Lancefield groups A through H and K through V. Whereas the more significant streptococcal pathogens of
humans are in groups A and B.
Group A Streptococcus:
Streptococcus pyogenes:
S. pyogenes is a coccus that forms white colonies 1–2 mm in diameter surrounded by a large zone of beta-
hemolysis after 24 hours on blood agar plates. Pathogenic strains of this species often form capsules.
Pathogenicity:
•Adhesion: Interaction with host fibronectin, a matrix protein on eukaryotic cells, is considered the
principal mechanism by which Str. pyogenes binds to epithelial cells of the pharynx and skin. The
structure that recognizes host fibronectin is located on the F protein. The interaction between the
streptococcal F protein and host cell fibronectin also mediates internalization of the bacteria into host
cells.
Two main structural features enable cells of S. pyogenes to evade phagocytosis:
• M protein: A membrane protein called M protein destabilizes complement, thereby interfering with
opsonization and lysis.
• Hyaluronic acid capsule: Because hyaluronic acid is normally found in the body, white blood cells may
ignore bacteria.
• Streptokinases: Two streptokinases that break down blood clots, presumably enabling group A
Streptococcus to rapidly spread through infected and damaged tissues.

• Deoxyribonucleases: Four distinct deoxyribonucleases depolymerize DNA that has been released from
dead cells in abscesses, reducing the firmness of the pus surrounding the bacteria and facilitating
bacterial spread.
• C5a peptidase: C5a peptidase breaks down the complement protein C5a, which acts as a chemotactic
factor. Thus, S. pyogenes decreases the movement of white blood cells into a site of infection.
• Hyaluronidase: Hyaluronidase facilitates the spread of streptococci through tissues by breaking down
hyaluronic acid.
• pyrogenic toxins: Three distinct pyrogenic exotoxins SPE A, SPE B and SPE C that stimulate
macrophages and helper T lymphocytes to release cytokines that in turn stimulate fever, a widespread
rash, and shock. Because these toxins cause blood capillaries near the surface to dilate, producing a red
rash, some scientists call them erythrogenic toxins.
• Streptolysins: Str. pyogenes produces two distinct haemolysins, termed streptolysins O (oxygen labile)
and S (serum soluble), both of which lyse erythrocytes, polymorphonuclear leucocytes and platelets by
forming pores in their cell membrane. It releases streptolysins into the cytoplasm of the phagocyte,
causing lysosome to release their contents, which lyses the phagocyte and release the bacteria.
Epidemiology:
Group A Streptococcus frequently infects the pharynx or skin.
Streptococcus pyogenes causes disease only when normal competing microbiota are depleted, when a large
inoculum enables the streptococci to gain a rapid foothold before antibodies are formed against them, or
when adaptive immunity is impaired.
S. pyogenes can invade deeper tissues and organs through a break in skin and mucous membrane barriers.
People spread S. pyogenes among themselves via respiratory droplets, especially under crowded conditions,
such as those in classrooms and day care centres.
Diseases:
Pharyngitis: A sore throat caused by streptococci, commonly known as “strep throat,” is a kind of
pharyngitis — inflammation of the pharynx—that is accompanied by fever, malaise, and headache. The back
of the pharynx typically appears red, with swollen lymph nodes and purulent (pus-containing) abscesses
covering the tonsils.
Scarlet Fever: The disease known as scarlet fever or as scarlatina often accompanies streptococcal
pharyngitis when the infection involves a lysogenized strain of S. pyogenes. After one to two days of
pharyngitis, pyrogenic toxins released by the streptococci trigger a diffuse rash that typically begins on the
chest and spreads across the body. The tongue usually becomes strawberry red. The rash disappears after
about a week and is followed by sloughing of the skin.

Pyoderma and Erysipelas: A pyoderma is a confined, pus-producing lesion that usually occurs on the
exposed skin of the face, arms, or legs. One cause is group A streptococcal infection following direct contact
with an infected person or contaminated fomites. After a pus-filled lesion breaks open, it forms a yellowish
crust. This stage is highly contagious.
When a streptococcal infection also involves surrounding lymph nodes and triggers pain and inflammation,
the condition is called erysipelas.
Streptococcal Toxic-Shock Syndrome: Group A streptococci can spread, albeit rarely, from an initial site
of infection, particularly in patients infected with HIV or suffering with cancer, heart disease, pulmonary
disease, or diabetes mellitus. Such spread leads to bacteremia and severe multisystem infections producing
streptococcal toxic-shock syndrome (STSS).
Patients experience inflammation at sites of infection as well as pain, fever, chills, malaise, nausea,
vomiting, and diarrhoea. These signs and symptoms are followed by increased pain, organ failure, shock—
and over 40% of patients die.
Necrotizing Fasciitis: In this disease, streptococci enter the body through breaks in the skin, secrete
enzymes and toxins that destroy tissues, and eventually destroy muscle and fat tissue. The bacteria spread
deep within the body along the fascia.
Necrotizing fasciitis also involves toxemia (toxins in the blood), failure of many organs, and death of more
than 50% of patients.
Rheumatic Fever: A complication of untreated S. pyogenes pharyngitis is rheumatic fever, in which
inflammation leads to damage of heart valves and muscle. Though the exact cause of the damage is
unknown, it appears that rheumatic fever is not caused directly by Streptococcus but instead is an
autoimmune response in which antibodies directed against streptococcal antigens cross-react with heart
antigens. Damage to the heart valves may be so extensive that they must be replaced when the patient
reaches middle age.
Glomerulonephritis: For an undetermined reason, antibodies bound to the antigens of some strains of
group A Streptococcus are not removed from circulation but instead accumulate in the glomeruli of the
kidneys’ nephrons. The result is glomerulonephritis— inflammation of the glomeruli and nephrons—
which obstructs blood flow through the kidneys and leads to hypertension and low urine output.
Diagnosis:
➢ Because Streptococcus is not a normal member of the microbiota of the skin, the observation of Gram-
positive bacteria in short chains or pairs in cutaneous specimens can provide a rapid preliminary
diagnosis of pyoderma, erysipelas, and necrotizing fasciitis.
➢ Physicians use an immunological test called a rapid strep test that identifies the presence of group A
streptococcal antigens.

➢ Antibodies against streptolysin O (The ASO test) are used to documents antecedent streptococcal
infection in the throat of patient with clinical sign of rheumatic fever.
➢ Detection of increased level of serum antibodies to streptococcal hyaluronidase and
deoxyriboneuclease is also of diagnostic importance.
Treatment:
•Penicillin is very effective against S. pyogenes.
•Erythromycin or cephalosporin is used to treat penicillin-sensitive patients.
•S. pyogenes is also susceptible to the topical antimicrobial bacitracin—a characteristic that distinguishes
it from group B Streptococcus.
•Necrotizing fasciitis must be treated with aggressive surgical removal of nonviable tissue and infecting
bacteria.
Prevention:
Hygienic measures: Skin infections with Str. pyogenes are usually associated with poor hygiene, and can
to a large extent be prevented by standard hygienic measures.
Chemoprophylaxis: As the primary attack of rheumatic fever usually occurs during childhood, long-term
penicillin prophylaxis until adulthood is recommended to reduce the risk of further attacks and further heart
injury.
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Group B Streptococcus:
Streptococcus agalactiae
Group B Streptococcus, or S. Agalactiae is a Grampositive coccus, 0.6–1.2 μm in diameter, that divides
to form chains. Like group A Streptococcus, S. agalactiae is beta-hemolytic, but it can be distinguished
from the former by three qualities:
1. It has group-specific, polysaccharide cell wall antigens.
2. It forms buttery colonies that are 2–3 mm in diameter and have a small zone of beta-hemolysis after 24
hours of growth on blood agar.
3. It is bacitracin resistant.
Pathogenicity:
•Even though S. agalactiae forms capsules, antibodies target its capsular antigens, so the capsules are not
protective. For this reason S. agalactiae has a predilection for newborns who have not yet formed type-
specific antibodies and whose mothers are uninfected.

•Group B streptococci produce enzymes—proteases (that catabolise protein), hemolysins,
deoxyribonuclease, and hyaluronidase—that probably play a role in causing disease.
Epidemiology:
o Group B streptococci normally colonize the lower gastrointestinal (GI), genital, and urinary tracts.
Diseases in adults primarily follow wound infections and childbirth.
o Sixty percent of newborns are inoculated with group B streptococcal strains either during passage
through the birth canal or by health care personnel.
o Infections in newborns less than one week old cause early-onset disease; infections occurring in
infants one week to three months of age cause late-onset disease.
Diseases:
Infection in the neonate:
Two different entities are recognized:
1. Early-onset disease, most cases of which present at or within 12 h of birth.
2. Late-onset disease, presenting more than 7 days and up to 3 months after birth.
Early-onset disease: This results from ascending spread of Str. agalactiae from the vagina into the
amniotic fluid, which is then aspirated by the infant and results in septicaemia in the infant or the mother,
or both.
Depending on the site of initial contamination, neonates may be ill at birth or develop acute and fulminating
illness a few hours, or a day or two, later. The clinical symptoms include lethargy, cyanosis and apnoea.
Late-onset disease: Purulent meningitis is the most common manifestation, but septic arthritis,
osteomyelitis, conjunctivitis, sinusitis, otitis media, endocarditis and peritonitis also occur.
Infections in the adult:
Ascending spread of Str. agalactiae leading to amniotic infection may result in abortion, chorioamnionitis,
post-partum sepsis.
Diagnosis:
▪ Medical laboratory technologists identify group B streptococcal infections by means of ELISA tests
utilizing antibodies directed against the bacteria’s distinctive cell wall polysaccharides.
▪ Samples of clinical specimens can also be incubated in blood media containing the antimicrobial drug
bacitracin, which inhibits the growth of other beta-hemolytic bacteria.
Treatment:
Penicillin or ampicillin work against group B Streptococcus, though some strains tolerate concentrations of
the drugs more than 10 times greater than that needed to inhibit group A Streptococcus.
For this reason, physicians may prescribe vancomycin instead of penicillin.
Prevention:

▪The Centers for Disease Control (CDC) recommends prophylactic administration of penicillin at birth
to children whose mothers’ urinary tracts are colonized with group B streptococci.
▪Additionally, physicians can immunize women against group B streptococci, preventing infection of
future children.
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Streptococcus pneumoniae:
➢ The bacterium is a Gram-positive coccus, 0.5–1.2 μm in diameter, that forms short chains or, more
commonly, pairs.
➢ Colonies of S. pneumoniae grown for 24 hours are 1–3 mm in diameter, round, mucoid,
unpigmented, and dimpled in the middle because of the death of older cells.
➢ Colonies are alpha haemolytic on blood agar when grown aerobically and beta haemolytic when
grown anaerobically.
Pathogenicity:
➢ Streptococcus pneumoniae is a normal member of the pharyngeal microbiota that can colonize the
lungs, sinuses, and middle ear.
➢ The cells of virulent strains of S. pneumoniae are surrounded by a polysaccharide capsule, which
protects them from digestion after endocytosis.
➢ Cells of S. pneumoniae insert into their cell walls a chemical called phosphorylcholine. Its binding
to receptors on cells in the lungs, in the meninges, and blood vessel walls stimulates the cells to
engulf the bacteria.
➢ Together, the polysaccharide capsule and phosphorylcholine enable pneumococci to “hide” inside
body cells. S. pneumoniae can then pass across these cells into the blood and brain.

➢ Protein adhesion,that mediates binding of the cells to epithelial cells of the pharynx. From there
the bacteria enter the lungs.
➢ The bacterium counteracts this defense by secreting secretory IgA protease, which destroys IgA.
➢ Pneumolysin, which binds to cholesterol in the cytoplasmic membranes of ciliated epithelial cells,
producing transmembrane pores that result in the lysis of the cells.
Epidemiology:
Streptococcus pneumoniae grows in the mouths and pharynges of 75% of humans, without causing
harm; however, when pneumococci travel to the lungs, they cause disease.
Diseases:
Pneumococcal Pneumonia
➢ As the bacteria multiply in the alveoli (air sacs), they damage the alveolar lining, allowing fluid, red
blood cells, and leukocytes to enter the lungs.
➢ The leukocytes attack Streptococcus, in the process secreting inflammatory and pyrogenic
chemicals.
➢ The onset of clinical symptoms is abrupt and includes a fever of 39–41°C and severe shaking chills.
➢ Most patients have a productive cough, slightly bloody sputum, and chest pain.
Sinusitis and Otitis Media:
➢ Following viral infections of the upper respiratory tract, S. pneumoniae can also invade the sinuses
and middle ear, where it causes sinusitis and otitis media.
➢ Pus production and inflammation in these cavities create pressure and pain.
Bacteremia and Endocarditis:
➢ Streptococcus pneumoniae can enter the blood either through lacerations or as a result of tissue
damage in the lungs during pneumonia.
➢ As with Staphylococcus, S. pneumoniae can colonize the lining of the heart, causing endocarditis.
The heart valves, once involved, are typically destroyed.
Pneumococcal Meningitis:
Pneumococci can spread to the meninges via bacteremia, during sinusitis or otitis media, or following
head or neck surgery or trauma that opens a passage between the pharynx and the subarachnoid space
of the meninges.
Diagnosis:
➢ Gram stains of sputum smears and confirm their presence with the Quellung reaction, in which
anticapsular antibodies cause the capsule to swell.
➢ Antibody agglutination tests can also be used to identify specific strains.

➢ Laboratory technologists can distinguish pneumococcal colonies from other colonies of alpha-
haemolytic strains by adding a drop of bile to a colony. Bile triggers chemicals present in
pneumococci to lyse the cells, dissolving the colony in just a few minutes.
Treatment:
➢ Penicillin has long been the drug of choice against S. Pneumoniae.
➢ Cephalosporin
➢ Erythromycin bind to 50S ribosome and hinder translocation of the elongated peptide chain back
from ‘A’ site to ‘P’ site and the ribosome does not move along the mRNA to expose the next codon.
➢ Chloramphenicol binds to 50S subunit—interferes with peptide bond formation and transfer of
peptide chain from ‘P’ site.
Prevention:
Prevention of pneumococcal diseases is focused on a vaccine made from purified capsular material from
the 23 most common pathogenic strains. The vaccine is immunogenic and long lasting in normal adults,
but unfortunately it is not as efficacious in patients at greatest risk, such as the elderly, young children, and
AIDS patients.
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Bacillus anthracis:
➢ Bacillus anthracis is a large (1 μm x3-3 x2-5 μm), rod-shaped, facultatively anaerobic,
endospore-forming bacterium that normally dwells in soil.
➢ Its cells are arranged singly, in pairs, or in chains .
➢ The tough external coat and the internal chemicals of endospores make these structures resistant to
harsh environmental conditions, enabling Bacillus to survive in the environment for centuries or
perhaps even longer.
➢ A vegetative (non-endospore) cell of Bacillus can survive in the body because it has multiple copies
of a plasmid (nonchromosomal DNA) coding for a capsule, which is composed solely of glutamic
acid. This capsule inhibits effective phagocytosis by white blood cells.
Epidemiology:
➢ B. anthracis spores introduced into the body by abrasion, inhalation or ingestion are phagocytosed
by macrophages and transported from the site of infection to regional lymph nodes, where the spores
germinate and vegetative bacteria multiply.
➢ The bacilli then enter the bloodstream causing massive septicaemia, with up to 108
colony forming
units/mL of blood.

Pathogenicity:
The pathogenicity of B. anthracis depends primarily on two major virulence factors:
1. The poly-D-glutamic acid capsule.
2. The toxin complex comprising three proteins: the protective antigen, oedema factor and lethal factor.
Oedema toxin and lethal toxin, formed by association of the protective antigen with the oedema factor and
lethal factor, respectively.
➢ The oedema toxin is thought to be responsible for the characteristic localised swelling associated
with cutaneous anthrax.
➢ Oedema factor is a calmodulin-dependent adenylate cyclase that catalyses the production of
intracellular cyclic adenosine monophosphate (cAMP) from host adenosine triphosphate (ATP),
inducing interleukin (IL)-6 and inhibiting tumour necrosis factor (TNF)-α in monocytes.
➢ The lethal toxin that is believed to play the major role in damage to the host and death.
➢ Lethal factor is a zinc metalloprotease that inactivates mitogen-activated protein kinase kinase,
particularly in macrophages.
➢ The lethal toxin stimulates macrophages to produce IL-1β and TNF-α. During infection, IL-1β
accumulates within macrophages and TNF-α is released.
➢ As the concentration of lethal toxin increases later in the infection process, macrophage lysis
produces a sudden release of IL-1β, causing shock and death.
The pathogenesis of anthrax is related to the sensitivity of macrophages to:
• the antiphagocytic activity of the capsule.
• the adenylate cyclase activity of the oedema toxin.
• the metalloprotease activity of the lethal toxin.
Diseases:
Gastrointestinal anthrax: is very rare in humans but is common in animals; it results in intestinal
hemorrhaging and eventually death.
Inhalation anthrax: is also rare in humans, as it requires inhalation of airborne endospores. After
endospores germinate in the lungs, they secrete toxins that are absorbed into the bloodstream, producing
toxemia.
Early signs and symptoms include fatigue, malaise, fever, aches, and cough—all of which are common to
many pulmonary diseases. In a later phase, victims of inhalation anthrax have a high fever and labored
breathing due to localized swelling, and they go into shock.
Cutaneous anthrax: Begins when a painless, solid, raised nodule forms on the skin at the site of infection.
The cells in the affected area die, and the nodule spreads to form a painless, swollen, black, crusty ulcer

called an eschar. B. anthracis growing in the eschar releases anthrax toxin into the blood, producing
toxemia.
Meningitis: Haemorrhagic meningitis may complicate any form of anthrax infection, when the bacteraemia
spreads across the blood-brain barrier to the central nervous system (CNS).
A striking pathological sign of anthrax meningitis is termed the Cardinal’s cap characterized by dark-red
extensive haemorrhaging beneath the lining of the skull.
Diagnosis:
➢ Gram’s stain may show typical large Gram-positive bacilli, and culture on blood agar yields the
large, flat, greyish, ‘ground-glass’ colonies with the characteristic ‘medusa head’ appearance.
➢ Demonstration of non-motility, gelatin liquefaction, growth in straight chains and enhanced growth
aerobically, as seen in the characteristic inverted fir tree appearance in a gelatin stab, will generally
identify B. anthracis completely.
➢ Serological diagnosis is done by enzyme-linked immunosorbent assay (ELISA).
➢ For the rapid identification of bacteria and diagnosis of disease, the polymerase chain reaction
should be used.
Treatment:
➢ Penicillin remains the drug of choice, as β- lactamase-producing strains of B. anthracis are rare.
➢ Most strains are also sensitive to macrolides, aminoglycosides, tetracyclines and
chloramphenicol.
➢ Ciprofloxacin (or a similar fluoroquinolone) is recommended as prophylaxis or early treatment
for those considered at greatest risk of exposure following a large-scale release of anthrax spores in
a deliberate attack.
Prevention:
Prevention of naturally occurring disease in humans requires control of the disease in animals. Farmers in
areas where anthrax is endemic must vaccinate their stock and bury or burn the carcasses of infected
animals.
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Corynebacterium:
➢ Corynebacterium diphtheriae is a pleomorphic, non-endospore-forming bacteria that are
ubiquitous on plants and in animals and humans, where they colonize the skin and the respiratory,
gastrointestinal, urinary, and genital tracts.

➢ The bacteria divide via a type of binary fission called snapping division, in which daughter cells
remain attached to form characteristic V-shapes and side-by-side palisade arrangements.
➢ C. diphtheriae is aerobic and facultatively anaerobic, growing best on a blood- or serum-
containing medium at 35–37°C with or without carbon dioxide enrichment.
Pathogenesis
To cause disease C. diphtheriae must:
• invade, colonize and proliferate in local tissues
• be lysogenized by a specific β-phage, enabling it to produce toxin.
In the upper respiratory tract, diphtheria bacilli elicit an inflammatory exudate and cause necrosis of the
cells of the faucial mucosa.
The diphtheria toxin possibly assists colonization of the throat or skin by killing epithelial cells or
neutrophils.
➢ The diphtheria toxin is a heat-stable polypeptide, composed of two fragments: A (active) and B
(binding).
➢ The toxin binds to a specific receptor on susceptible cells and enters by receptor-mediated
endocytosis.
➢ The A subunit is cleaved and released from the B subunit as it inserts and passes through the
lysosomal membrane into the cytoplasm.
➢ Fragment A catalyses the transfer of adenosine disphosphate (ADP)-ribose from nicotinamide
adenine dinucleotide (NAD) to the eukaryotic elongation factor 2, which inhibits the function of the
latter in protein synthesis.
➢ Inhibition of protein synthesis is probably responsible for both the necrotic and neurotoxic effects
of the toxin.
➢ Production of toxin by lysogenized C. diphtheriae is enhanced considerably when the bacteria are
grown in low iron conditions. Other factors such as osmolarity, amino acid concentrations and pH
have a role.
Diseases:
➢ Respiratory infections are most severe, resulting in the sudden and rapid signs and symptoms of
diphtheria, including fever, pharyngitis, and the oozing of a fluid composed of intracellular fluid,
blood clotting factors, leukocytes, bacteria, and the remains of dead cells of the throat.
➢ The fluid thickens into a pseudomembrane that can adhere tightly to the underlying tissues,
completely occluding the respiratory passages and resulting in death by suffocation.
Diagnosis:

➢ Initial diagnosis is based on the presence of a pseudomembrane.
➢ Culture of specimens on Loffler’s medium, which was developed especially for the culture of C.
diphtheriae, produces distinct colonial morphologies.
➢ Absolute certainty of diagnosis results from an immunodiffusion assay, called an Elek test, in
which antibodies against the toxin react with toxin in a sample of fluid from the patient.
Treatment:
➢ The most important aspect of treatment is the administration of antitoxin (immunoglobulins against
the toxin) to neutralize toxin before it binds to cells; once the toxin binds to a cell, it enters via
endocytosis and kills the cell.
➢ Penicillin or erythromycin kills the bacterium, preventing the synthesis of more toxin.
➢ In severe cases, a blocked airway must be opened surgically or bypassed with a tracheostomy
tube.
Prevention:
Toxoid (deactivated toxin) is administered in five injections as part of the DTaP vaccine, which combines
diphtheria and tetanus toxoids with antigens of the pertussis bacterium, at 2, 4, 6, 18, and about 60 months
of age, followed by booster immunizations with a slightly different vaccine (Tdap) every 10 years.
Mycobacterium:
Mycobacterium is non-endospore-forming pathogen
Species in this genus have cell walls containing an abundance of a waxy lipid, called mycolic acid that is
composed of chains of 60 to 90 carbon atoms.
Specifically, mycobacteria do the following:
• Grow slowly (because of the time required to synthesize numerous molecules of mycolic acid). The
generation time varies from hours to several days.
• Are protected from lysis once they are phagocytized.
• Are capable of intracellular growth.
• Are resistant to Gram staining, detergents, many common antimicrobial drugs. The acid-fast staining
procedure was developed to differentially stain mycobacteria.
M. tuberculosis and M. leprae, which cause tuberculosis and leprosy, respectively.
Mycobacterium tuberculosis:
➢ Tuberculosis (TB), the primary mycobacterial disease, is fundamentally a respiratory disease
caused by Mycobacterium tuberculosis.

➢ This bacterium forms dull-yellow raised colonies after growth for weeks on a special differential
medium called Lowenstein-Jensen agar.
➢ Virulent strains of M. tuberculosis have a cell wall component, called cord factor, that produces
strands of daughter cells that remain attached to one another in parallel alignments.
➢ Cord factor also inhibits migration of neutrophils and is toxic to mammalian cells.
The process involves development of tuberculosis in lungs:
Primary tuberculosis:
1 Mycobacterium typically infects the respiratory tract via inhalation of respiratory droplets formed when
infected individuals talk, sing, cough, or sneeze. A respiratory droplet is about 5 mm in diameter and carries
one to three bacilli. The minimum infectious dose is about 10 cells. Mycobacterium has adhesive pili that
attach to an extracellular human protein, laminin.
2 Macrophages in the alveoli (air sacs) of the lungs phagocytize the pathogens but are unable to digest them
in part because the mycobacteria prevent fusion of lysosomes with phagosomes. M. tuberculosis also
invades cells lining the alveoli.
3 The bacteria replicate freely within host cells, gradually killing them. Infected cells of the alveolar lining
release chemokines that attract more macrophages. Bacteria released from dead macrophages are
phagocytized by other macrophages, beginning the cycle anew. This stage of infection, which lasts for a
few weeks, is typically asymptomatic or associated with a mild fever.
4 Infected macrophages present antigen to T lymphocytes, which produce lymphokines that attract and
activate more macrophages and trigger inflammation. Tightly appressed macrophages surround the site of
infection, forming a tubercle.
5 Other cells of the body deposit collagen fibers, enclosing infected macrophages and lung cells within the
tubercle.
Infected cells in the center of the tubercle die, releasing M. tuberculosis and producing caseous necrosis—
the death of tissue that takes on a cheeselike consistency because of the presence of protein and fat released
from dying cells.
Sometimes, for an unknown reason, the center liquefies and subsequently becomes filled with air. Such a
tubercle is called a tuberculous cavity.
Secondary or Reactivated Tuberculosis: Secondary tuberculosis results when M. tuberculosis breaks the
stalemate, ruptures the tubercule, and reestablishes an active infection in which the bacteria spread through
the lungs via the bronchioles.
Reactivated TB is a common occurrence in TB-infected individuals with suppressed immune systems.
Disseminated Tuberculosis: Disseminated TB results when some macrophages carry the pathogens via
the blood and lymph to a variety of sites, including the bone marrow, spleen, kidneys, spinal cord, and

brain. The signs and symptoms observed in disseminated TB correspond to complications arising at the
various sites involved.
Diagnosis, Treatment, and Prevention
➢ A tuberculin skin test is used to screen patients for possible exposure to tuberculosis. In this test,
a health care worker injects about 0.1 ml of cell wall antigens from M. tuberculosis into a patient’s
skin. The appearance of a hard, red swelling at the test site within 24 to 72 hours is a positive test.
➢ Chest X rays can reveal the presence of tubercles in the lungs; primary tuberculosis appears as
tubercles in the lower and central areas of the lungs, whereas secondary tuberculosis more
commonly appears higher in the lungs.
➢ The presence of acid-fast cells and cords in sputum confirms an active case of tuberculosis.

Physicians use antibacterial drugs prophylactically to treat patients who have either shown a recent
conversion from a negative to a positive tuberculin skin test or undergone significant exposure to active
cases of tuberculosis.
In countries where tuberculosis is common, health care workers immunize patients with BCG (bacillus of
Calmette and Guérin )vaccine.
------------------------------------------------------------------------------------------------------------------------------
Mycobacterium leprae:
➢ Mycobacterium leprae —which is also called by the less dreaded name Hansen’s disease, after
Gerhard Hansen , a Norwegian bacteriologist who discovered its cause in 1873.
➢ M. leprae is a Grampositive bacillus.
➢ Because of the abundance of mycolic acid in the cell wall, these bacilli do not Gram stain purple
and must instead be stained with an acid-fast stain.
➢ M. leprae grows best at 30°C, showing a preference for cooler regions of the human body,
particularly peripheral nerve endings and skin cells in the fingers, toes, lips, and earlobes.
➢ Leprosy has two different manifestations depending on the immune response of the patient:

➢ Patients with a strong cellmediated immune response are able to kill cells infected with the
bacterium, resulting in a nonprogressive form of the disease called tuberculoid leprosy.
➢ Regions of the skin that have lost sensation as a result of nerve damage are characteristic of this
form of leprosy.
➢ Patients with a weak cell-mediated immune response develop lepromatous leprosy , in which
bacteria multiply in skin and nerve cells, gradually destroying tissue and leading to the progressive
loss of facial features, digits (fingers and toes), and other body structures. Development of signs and
symptoms is very slow; incubation may take years before the disease is evident.
Diagnosis, Treatment, and Prevention:
➢ Diagnosis of leprosy is based on signs and symptoms of disease—a loss of sensation in skin lesions
in the case of tuberculoid leprosy and disfigurement in the case of lepromatous leprosy.
➢ Diagnosis is confirmed by a positive skin test with leprosy antigen (similar to the tuberculin skin
test) or through direct observation of acid-fast rods (AFRs) in tissue samples or nasal secretions (in
the case of lepromatous leprosy).
➢ BCG vaccine provides some protection against leprosy (as well as against tuberculosis), but
prevention is achieved primarily by limiting exposure to the pathogen and by the prophylactic use
of antimicrobial agents when exposure occurs.
-----------------------------------------------------------------------------------------------------------------------------
Clostridium botulinum:
Clostridium botulinum is an anaerobic, endospore- forming, Gram-positive bacillus that is common in soil
and water worldwide. Its endospores survive improper canning of food, germinating to produce vegetative
cells that grow and release into the jar or can a powerful neurotoxin that causes botulism.

Strains of C. botulinum produce one of seven antigenically distinct
botulism toxins (A through G).
Pathogenesis:
1. A nerve impulse from the central nervous system causes vesicles filled with acetylcholine to fuse with
the neuron’s cytoplasmic membrane,
2. releasing acetylcholine into the synaptic cleft. The binding of acetylcholine to receptors on the muscle
cell’s cytoplasmic membrane stimulates a series of events that result in contraction of the muscle cell.
Botulism toxin blocks the fusion of the vesicles with the neuron’s cytoplasmic membrane, thereby
preventing secretion of the neurotransmitter into the synaptic cleft; as a result, the muscle cell does not
contract.
Types:
1. foodborne botulism,
2. infant botulism,
3. and wound botulism
Foodborne botulism occurs usually within one to two days following the consumption of toxin in home-
canned foods or preserved fish.
Contaminated food may not appear or smell spoiled. Patients are initially weak and dizzy and have blurred
vision, dry mouth, dilated pupils, constipation, and abdominal pain, followed by a progressive paralysis
that eventually affects the diaphragm.

Infant botulism results from the ingestion of endospores, which then germinate and colonize the infant’s
gastrointestinal (GI) tract. Infants are susceptible to colonization because their GI tracts do not have a
sufficient number of benign microbiota to compete with C. botulinum for nutrients and space.
Botulism toxin is absorbed into the blood from an infected infant’s GI tract, causing nonspecific symptoms:
crying, constipation.
Wound botulism usually begins four or more days following the contamination of a wound by endospores.
Diagnosis:
The symptoms of botulism are diagnostic; culturing the organism from contaminated food, from faeces, or
from the patient’s wounds confirms the diagnosis.
Further, toxin activity can be detected by using a mouse bioassay.
Treatment:
Treatment of botulism entails three approaches:
• Repeated washing of the intestinal tract to remove Clostridium.
• Administration of antibodies against botulism toxin to neutralize toxin in the blood before it can bind to
neurons.
• Administration of antimicrobial drugs to kill clostridia in infant and wound botulism cases.
Clostridium perfringens:
➢ Clostridium perfringens , the clostridium most frequently isolated from clinical specimens, is a
large, almost rectangular, Gram-positive bacillus.
➢ Although it is nonmotile, its rapid growth enables it to proliferate across the surface of laboratory
media, resembling the spread of motile bacteria.
➢ Endospores are rarely observed either in clinical samples or in culture.
➢ C. perfringens type A, known by its specific antigens, is the most virulent serotype.
Pathogenesis and Epidemiology:
➢ C. perfringens produces 11 toxins that lyse erythrocytes and leukocytes, increase vascular
permeability, reduce blood pressure, and kill cells, resulting in irreversible damage.
➢ C. Perfringens commonly grows in the digestive tracts of animals and humans; it is nearly
ubiquitous in fecally contaminated soil and water.
Diseases:
➢ Clostridial food poisoning is a relatively benign disease characterized by abdominal cramps and
watery diarrhoea but not fever, nausea, or vomiting.

➢ C. perfringens is not invasive, but when some traumatic event introduces endospores into the body,
they can germinate in the anaerobic environment of deep tissues.
➢ The immediate result is intense pain at the initial site of infection as clostridial toxins induce
swelling and tissue death.
➢ The rapidly reproducing bacteria can then spread into the surrounding tissue, causing the death of
muscle and connective tissue that is typically accompanied by the production of abundant, foul-
smelling, gaseous, bacterial waste products—hence the common name for the disease: gas
gangrene.
➢ Shock, kidney failure, and death can follow, often within a week of infection.
Diagnosis:
❑ Clostridium is involved in food poisoning by demonstrating more than 105
bacteria in a gram of
food or 106
cells per gram of faeces.
❑ The appearance of gas gangrene is usually diagnostic by itself, though the detection of large Gram-
positive bacilli is confirmatory.
Treatment:
❖ Clostridial food poisoning is typically self-limiting—the pathogens and their toxins are eliminated
in the resulting watery stool.
❖ Physicians must quickly and aggressively intervene to stop the spread of necrosis in gas gangrene
by surgically removing dead tissue and administering large doses of antitoxin and penicillin.
❖ Oxygen applied under pressure may also be effective.
Prevention:
➢ Refrigeration of food prevents toxin formation and reduces the chance of clostridial food poisoning.
➢ Alternatively, reheating contaminated food destroys any toxin that has formed.
➢ Gas gangrene occurs when endospores are introduced deep in the tissues, proper cleaning of wounds
can prevent many cases.
--------------------------------------------------------------------------------------------------------------------------
Clostridium difficile:
❑ Clostridium difficile is a motile, anaerobic intestinal bacterium with cells about 1.5 μm in width
and 3–6.5 μm in length that form oval, subterminal endospores.
❑ The bacterium produces two toxins (called toxins A and B) and the enzyme hyaluronidase.
Pathogenesis, Epidemiology, and Disease:

❖ C. diff. is a common member of the intestinal microbiota, it can be an opportunistic pathogen in
patients treated with broad-spectrum antimicrobial drugs, such as penicillin and cephalosporin.
❖ In minor infections these lesions result in recurrent, persistent, explosive diarrhoea.
❖ C. difficile produces life-threatening pseudomembranous colitis, in which large sections of the
colon wall slough off, potentially perforating the colon, and leading to massive internal infection
by fecal bacteria and eventual death.
❖ C. diff. is a major cause of death of elderly patients.
Diagnosis:
➢ Diarrhoea in patients undergoing antimicrobial therapy is suggestive of C. difficile infection.
➢ Laboratory microbiologists confirm the diagnosis either by isolating the organism from feces
using selective media or by demonstrating the presence of the toxins via immunoassays.
Treatment:
❑ Discontinuation of the implicated antimicrobial drug, which allows the microbiota to return to
normal, usually resolves minor infections with C. difficile.
❑ More serious cases are treated with either oral vancomycin or metronidazole, though endospores
survive such therapy in about a third of patients, causing a relapse.
Prevention:
❖ C. difficile is frequently found in hospitals, and hospital personnel can easily transmit it between
patients. Proper hygiene— particularly frequent hand washing—is critical for limiting nosocomial
infections.
❖ Endospores survive ordinary floor cleaners; bleach is effective in killing them.
---------------------------------------------------------------------------------------------------------------------------
Clostridium tetani:
➢ Clostridium tetani is a small, motile, obligate anaerobe that produces a terminal endospore, giving
the cell a distinctive lollipop appearance.
➢ C. tetani is ubiquitous in soil, dust, and the GI tracts of animals and humans.
➢ Its vegetative cells are extremely sensitive to oxygen and live only in anaerobic environments, but
its endospores survive for years.
➢ Its toxin causes the disease tetanus.
Pathogenesis:

➢ Endospores of C. tetani access to an anaerobic environment in which they germinate, grow, and
produce a fatal disease caused by tetanospasmin (tetanus toxin)—a potent neurotoxin released by
C. tetani cells when they die.
➢ The secretion of acetylcholine by motor neurons at neuromuscular junctions stimulates muscles to
contract. Nerves can only stimulate muscles; there is no inhibitory neurotransmitter released at the
junction that could relax a nuclear contraction.
➢ In contrast, a motor neuron can be inhibited by other neurons that released inhibitory
neurotransmitters in the brain or spinal cord.
➢ Tetanospasmin released from C. tetani is composed of two polypeptides held together by a disulfide
bond.
➢ The heavier of the two polypeptides binds to a receptor on a neuron’s cytoplasmic membrane.
➢ The neuron then endocytizes the toxin, removes the lighter of the two polypeptides, and transports
the lighter portion to the central nervous system.
➢ There the small polypeptide enters an inhibitory neuron and blocks the release of inhibitory
neurotransmitter.
➢ With inhibition blocked, excitatory activity is unregulated, and muscles are signaled to contract
simultaneously.
➢ The result is that muscles on both sides of joints contract and do not relax.
➢ Opposing contractions can be so severe that they break bones.

Disease and Epidemiology:
➢ The incubation period of tetanus ranges from a few days to a week depending on the distance of the
site of infection from the central nervous system.
➢ Typically the initial and diagnostic sign of tetanus is tightening of the jaw and neck muscles—which
is why tetanus is also called lockjaw.
➢ Other early symptoms include sweating, drooling, grouchiness, and constant back spasms.
➢ Complete, unrelenting contraction of the diaphragm results in a final inhalation; patients die because
they cannot exhale.
➢ If the toxin spreads to autonomic neurons, then heartbeat irregularities, fluctuations in blood
pressure, and extensive sweating result.
➢ Spasms and contractions may spread to other muscles, becoming so severe that the arms and fists
curl tightly, the feet curl down, and the body assumes a stiff backward arch as the heels and back of
the head bend toward one another.
Diagnosis, Treatment, and Prevention:
➢ The diagnostic feature of tetanus is the characteristic muscular contraction, which is often noted too
late to save the patient.

➢ The bacterium itself is rarely isolated from clinical samples because it grows slowly in culture and
is extremely sensitive to oxygen.
❖ Treatment involves thorough cleaning of wounds to remove all endospores, immediate passive
immunization with immunoglobulin directed against the toxin, the administration of antimicrobials
such as penicillin, and active immunization with tetanus toxoid.
❑ The CDC currently recommends immunization with tetanus toxoid (five doses beginning at two
months of age, followed by a booster every 10 years for life).
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