Medicine II ◦ It is a slender gram-positive, anaerobic rod that may

COMMUNICABLE DISEASES develop a terminal spore – drumstick

Midterm Coverage – Dr. Fortuno o Under the microscope, the terminal spore is
AMS 204 spherical in one end and long and slender at the
other end. It would resemble a drumstick.
Coverage of Midterm Examination: o Since it is a gram-positive bacterium, it reacts to
I. Tetanus gram stain. Other gram-positive bacteria that are
II. Rabies usually found and affecting mankind are
III. Tuberculosis Staphylococcus, Streptococcus, and Clostridium
IV. Malaria ◦ It is sensitive to heat and cannot survive in the presence of
V. Sepsis oxygen. It is an anaerobic bacteria.
◦ It produces two exotoxins:
o Tetanolysin - its function is not known with
TETANUS certainty.
▪ Similar to Clostridium botulism but it does
History of Tetanus not produce the same manifestations as
◦ Egypt over 3000 years ago. Clostridium tetanii or tetanus infection
◦ It was again described by Hippocrates (tension) o Tetanospasmin - a neurotoxin that causes the
o Hippocrates was a great Greek physician and is clinical manifestations of tetanus.
▪ The more important exotoxin produced by
the Father of Western Medicine
Clostridium tetanii
o Formulated the Hippocratic oath
▪ It is a very heavy protein chain that is made
up of two bonds.
Note: Hippocrates noted that during the war between Greece and
Rome when the Roman soldiers invaded Greece, Roman and Greek • Short or light bond
soldiers after coming from the battle field suddenly developed some • Long or heavy bond
kind of tension (rigor, violent contractions that sometimes lead to ▪ These two bonds are bound together by a
broken bones) that is why tetanus is called tetanus because disulfate monovalent protein bond and if
Hippocrates was able to describe it as tension. you are going to break the chain then you
are already going to neutralize
◦ 1884, Carle and Rattone first noticed tetanus in animals tetanospasmin.
by injecting them with pus from a fatal human tetanus ▪ The divalent sulfate bond that bonds the two
case. chains together when cleaved will neutralize
the tetanospasmin.
Note: Carle and Rattone demonstrated the transmissibility of tetanus.
This is because of the transmission of the bacteria Clostridium tetani. Tetanospasmin: estimated human lethal dose – 2.5 ng/kg

Note: Tetanospasmin is very lethal. It can already cause death in

◦ Nicolaier produced tetanus in animals by injecting them with
persons as low as 2.5ng/kg.
samples of soil.
◦ 1889, Kitasato isolated the organism from a human victim
◦ Terminal spore is very resistant to heat and the usual anti-
and showed that it produced disease when injected into
septic. It cannot survive autoclaving at 121 °C for 20
animals. He reported that the toxin could be neutralized by
minutes but is relatively resistant to phenol & other chemical
specific antibodies.
agents.
o No amount of boiling for 15-20minutes is going to
Note: A Japanese physician Kitasato contributed a lot about tetanus.
destroy the spore but the bacteria can be
He noted that tetanus was indeed grown from the medium of
destroyed by heat. The spore found in the bacteria
Clostridium tetani and he was also able to report and formulate
is very resistant.
neutralizing antibodies against Clostridium tetani.
◦ It is widely distributed in soil and it remains nonpathogenic
until conditions are favorable for transformation into
◦ World War I (Germany, France, and England): only passive
vegetative form.
immunization was used for treatment and prophylaxis.
o Conditions that would make it more favorable:
▪ Less oxygen pressure in the environment
Note: During World War I, Kitasato was able to do his experiments
further and was able to prove that the antibodies against tetanus were
indeed effective in preventing disease and death among soldiers in
World War I

◦ 1924: Tetanus Toxoid was developed by Descombey and

it was then widely used during World War II (Germany and
other allied power and Japan and other allied power)
Causative Organism: Clostridium tetani

1|J K C P a l o m a r e s

Note: Under the microscope, it appears like a drumstick with a
spherical head and a long elongated end.
Pathogenesis of Tetanus
Note: The pathogenesis of tetanus starts when the bacteria enter the
body through a wound. Most of the time, there will be an entry point
that is visible. In 70% of cases of tetanus, the entry point is visible but
in 30% there is no entry point that is visible because simple abrasions
per se or even the licking of an animal, or even exposure of the mucus
membrane to the bacteria can be a passageway for the entry of
tetanus into the body. In anaerobic condition, the spores would
germinate. Once the spores germinate, the toxins are produced. The
toxins are the ones that cause the clinical manifestations of tetanus.
This will all be disseminated via the blood and the lymphatics and have
a propensity to reach the CNS because C.tetanus is the only one that
can cause a retrograde movement to the brain. The toxins act on
several sites within the CNS thus producing the different
manifestations of tetanus. The manifestations of tetanus are all
centered mainly on the CNS. This is why when the wound is nearer
the brain, the manifestation would appear much faster and worse as
compared to a wound further from the CNS.
◦ The typical clinical manifestations of tetanus are caused
when the toxin interferes with release of
neurotransmitters, thus blocking inhibitory impulses
o The neurotransmitters involved are the inhibitory
neurotransmitters. These are the ones that are
being blocked by the tetanospasmin.
◦ This leads to unopposed muscle contraction and spasm.
This can also potentially lead to death.
o Because of the increase in muscle contraction
through the inhibition of the inhibitory
neurotransmitters there is now an unopposed
contraction of the muscles. Because of the
unopposed muscle contraction, there will now be
the production of lactic acid. Lactic acid will cause
further deterioration in the patient.
◦ The toxins travel via intra-axonal transport at a rate of 75
– 250 mm/day; a process which takes 2 – 14 days to reach
the CNS
Note: The further the wound is from the CNS, the later the
manifestation of the disease would be.
Note: Clostridium tetani produces two toxins (tetanospasmin and
tetanolysin) but what is important in man is tetanospasmin. Once it
enters the body, it will start blocking. It will go to the presynpatic vesicle
and start blocking the inhibitory pathway. Since there is nothing that
will inhibit the contraction of the muscle, the muscles will always
remain in an excitatory state because the inhibitory transmitters are
supposed to counteract the excitatory state of the muscle. Since the
tetanospasmin blocks all of it, then the muscle will be in a state of
chronic contraction. A muscle that is in a state of chronic contraction
produces lactic acid. Even the lactic acid produced by the muscles will
be the ones that will cause the clinical manifestations of the patient.
Epidemiology
◦ Tetanus remains a major Public Health problem in the
developing world and is still encountered in the developed
world.
◦ In 1998, 215,000 deaths occurred with more than 50% of
these on the Africa continent. WHO estimated there were
213,000 tetanus deaths in 2002 with 198,000 occurring in
children < 5 years. As of the present, the disease is also
prevalent among persons aged 40 and older.
◦ Occurrence: Tetanus occurs worldwide but is most
frequently encountered in densely populated regions in hot,
damp climates with soil rich in organic matter.
Note: Tetanus remains a public health problem in the developing
world and it is still encountered in the developing world and developed
countries. It is a public health problem in the developing world due to
cultural practices that are very conducive to the development of
tetanus. Some African countries still practice putting animal dung
which is filled with C.tetani on the umbilicus of the baby after the
umbilical cord is cut. Clostridium tetani resides in the gut and any
manure from the gut will be infected with C.tetani. It is a public health
problem in the developed world because tetanus is a very preventable
disease where you can vaccinate everybody. Most of the cases in
America and Europe are because of: (1) immigrants coming from Asia,
ME, and South America (2) Patients who did not complete vaccination
against tetanus.
Occurrence:
◦ Tetanus occurs worldwide but is most frequently
encountered in densely populated regions in hot , damp
climates with soil rich in organic matter.
2|J K C P a l o m a r e s
 ◦ Reservoir : Organisms are found primarily in the soil and
intestinal tracts of animals and humans.
◦ Mode of Transmission: is primarily by:
o contaminated wounds
o Tissue injury
◦ Communicability: Tetanus is not contagious from person to
person .It is the only vaccine-preventable disease that is
infectious but not contagious.

Note: It is usually seen in places that have hot, damp climates with soil
rich in organic matter (usually in densely populated squatter areas,
slums, and farms). You seldom see tetanus cases in the coastal areas
of the Philippines. The organisms are found primarily in the soil and in
the intestinal tract of animals and humans. The intestinal tracts of
animals and humans are highly anaerobic which is a very good
medium or environment for them to thrive. Even if there is C.tetani in
the stomach and intestine, we do not develop the clinical
manifestations of tetanus because the first step in the pathogenesis of
◦ Tetanus death statistics worldwide:
tetanus is the entry of the bacteria through a wound or an abrasion or
o About 84,000 deaths from tetanus in Africa 2002
a cut. If there are no breaks in the intestinal system, we do not develop
(The World Health Report, WHO, 2004)
the clinical manifestations of tetanus. Mode of transmission: Primarily
o About 82,000 deaths from tetanus in South East
by contaminated wounds and tissue injury. It can also be through the
Asia 2002 (The World Health Report, WHO, 2004)
mucosal area. Communicability: tetanus is not contagious from person
o About 36,000 deaths from tetanus in Eastern
to person. It is the only vaccine preventable disease that is infectious
Mediterranean 2002 (The World Health Report,
but not contagious. It is highly transmissible. The vaccination against
WHO, 2004)
tetanus usually comes with Diphtheria and Pertussis (DTaP). For the
o About 11,000 deaths
elderly, the three must give vaccines are: (because the elderly are very
prone to falls and they often develop cuts; the antibody levels of the
Note: In terms of age, it is the disease of active ages and tetanus can
elderly are quite low so they are prone to developing different
also be seen in neonates and those who have given birth.
conditions): Pneumonia, Influenza, and Tetanus
Types of Tetanus
◦ Age : It is the disease of active age (5-40 years), Neonates, - Neonatal tetanus
female during delivery or abortion o Seen among neonates that suddenly fail to suck
◦ Males > females and have facial twitches, contractures from day 3
◦ Occupation : Agricultural workers are at higher rise up to day 28.
◦ Setting: Rural > Urban areas - Due to delivery
◦ Immunity: Herd immunity (community immunity) does not o Female who had just delivered a baby
protect the individual. o From day 0 up to 6 weeks after, the patient can
◦ Environmental and social factors: Unhygienic custom habits still contract tetanus because of the cutting of the
, Unhygienic delivery practices. umbilical cord.

Note: Males are commonly affected than females because of their

occupation. Most males do manual labor and most females stay at
home. Agricultural workers are at high risk for tetanus.

Herd immunity
- It is not able to protect an individual against tetanus
- Example: ½ is immune against tetanus while the other ½ is
not immune from tetanus. Will the other half be protected if
the other half is protected?
- Tetanus is very lowly immunogenic. Even if you had tetanus
before, you can still develop tetanus. It does not protect you
from further episodes of tetanus.
- NO herd immunity in tetanus because it has a very low
immunogenicity unlike the other conditions such as
Varicella, Measles which are highly immunogenic.

Philippines
- 80-90% covered against tetanus
Tetanus death

3|J K C P a l o m a r e s
 - 84,000 deaths from tetanus in Africa
o Contributes the greatest number of mortality in
terms of infectious diseases
- 82,000 deaths in Southeast Asia
- 36,000 deaths in the Mediterranean
- In the Philippines, tetanus ranks 46th cause of death.
Clinical Features
◦ Incubation period: 3 to 21 days, usually about 8 days.
o The clinical manifestations are seen after an
average of 8 days
◦ The further the injury site is from the CNS, the longer the
incubation period.
◦ Three types of Tetanus described:
o Local
▪ Patient with an abrasion on the arm and
there would be localized contractions on the
affected arm. This is a very minor
manifestation of tetanus.
o Cephalic
▪ More severe compared to local. The patient
has the manifestations of lock jaw, trismus,
and risus sardonicus. The patient will not
manifest with any bodily contractions, but
the contractions will just be localized in the
head area.
o General
▪ Most severe type of tetanus. There will be
manifestations of the local and cephalic
types seen in one patient.
Note: The clinical features start when the patient has difficulty in
opening or closing his mouth called the lock jaw. It is the first one felt
by the patient because it is closest to the CNS. Other manifestations
include neck stiffness, difficulty in swallowing, and muscle rigidity and
generalized muscle spasm.
Clinical features of generalized tetanus
Risus sardonicus Opisthotonos
(perpetual grin) (spastic paralysis of the back)
Diagnosis
◦ No laboratory findings are characteristic of tetanus.
Therefore, the diagnosis is entirely clinical and does not
depend upon bacteriologic confirmation.
◦ C. tetani is recovered from the wound in only 30% of
cases and can be isolated from asymptomatic patients.
o Even if you do culture, you will not be able to
recover the bacteria from the wound because 70%
of the time, wound culture would be negative.
o For bacterial infections, blood culture will only
yield 15-20% positive cultures. Blood culture will
take several days.
◦ Laboratory identification of the organism depends most
importantly on the demonstration of toxin production in mice.
◦ Clinically it is confirmed by noticing the following features:
o Risus sardonicus
o Lock jaw
o Opisthotonus
o Neck Rigidity
▪ Other disease that presents with neck
rigidity is meningitis
Note: There is no specific diagnostic test that you can do to diagnose
tetanus. When you diagnose a patient with tetanus, all you have to do
is to get a good history of a wound, abrasion, or cut on the patient’s
skin or the mucus membrane.
Complications
◦ Tetanus complication includes:
o Laryngospasm
▪ Needs to be intubated and connected to a
ventilator
o Fracture
▪ Because of the contracted state, the patient
may have fractures.
o Hypertension
▪ Tetanus also affects the autonomic nervous
system. The patient will have tachycardia
and hypertension because of the release of
cathecolamines into the circulation.
o Nosocomial infections
▪ Ventilator-associated pneumonia
▪ Decubitus ulcers
o Pulmonary Embolism
▪ Due to prolonged bed rest
▪ This is prevented by continuous ambulation
or passive bed exercise to the patient to
prevent hypercoagulability of the blood.
o Aspiration Pneumonia
o Death
Note: Most of the time, the patients die because of the complications
of tetanus.
Treatment
◦ Three goals of management:
o Neutralize the toxin: Two types that gives passive
immunity – directly inject Ig
4|J K C P a l o m a r e s
 ▪ administer Human tetanus immune globulin
(TIG) – less antigenic which causes less
cases of allergies if in the legs
▪ Equine immunoglobulin – cheaper; usually
seen in poor countries meteonidazole if above
o Eradicate C. tetani
o local wound care and administration of antibiotic tje waiste clindamycin
◦ Provide supportive care and maintain adequate nutrition
(antispasmodic drugs should be used and respiration
maintained by a breathing apparatus if necessary)
o The best medicine to be given to prevent
contractures is benzodiazepine but has a risk of
developing respiratory arrest.

Note: The vaccine is given by infiltrating ½ of the Ig into the wound

and ½ given IM. If there is no wound seen, given the whole dose IM.

Prevention
◦ Tetanus carries a 35% mortality rate, making prevention
very important!
◦ The best course is childhood immunization with consistent
booster doses and prompts cleaning of wounds.

TETANUS TOXOID (TT)

◦ Formalin-inactivated tetanus toxin

◦ Schedule
o Three or four doses + booster
o Booster every 10 years
◦ Efficacy
o Approximately 100%
◦ Duration
o Approximately 10 years

Should be administered with diphtheria toxoid as DTaP, DT, Td, or

Tdap

Routine Td Schedule for Unvaccinated Persons 7 Years of Age

and Older

Dose Interval
Primary 1 0
Primary 2 4 weeks (1 month)
Primary 3 6 to 12 months (1 year)

◦ Booster dose every 10 years

◦ For children 10 years of age and older ACIP recommends
that one of these doses (preferably the first) be administered
as Tdap

Case: Wounded patient with no prior vaccination. Give the inactivated

tetanus toxoid at 3 or 4 doses and booster every 10 years. Everyone
is at risk of developing tetanus.

RABIES

 Latin for madness

 derived from rabere - to rave
 Sanskrit: rabhas – violence

5|J K C P a l o m a r e s
  clinically diagnosed in 1903
 Adelchi Negri described the cytoplasmic eosinophilic
inclusions that now bear his name
 Negri bodies
 these were the only pathologic markers prior to the
development of the fluorescent antibody test in 1958
 Replaced by FAb test to clinically identify rabies

Note: The characteristic of a patient who has rabies is violence.

Epidemiology
 WHO : 55,000 humans die of rabies annually
 50,000 to 60,000 people die worldwide of rabies. Note: There is a significant drop in human rabies cases compared to
 Worldwide: the earlier years. This is because local governments are joining in drive
 Dogs (54%) against rabies. There are still cases of rabies mainly because of
 Most common animal vector of rabies cultural beliefs.
 Household dog>Street dog
 Wildlife (42%)
 Bats (4%)

Note: For the developed countries like the US and Canada, bites from
wild life animals such as skunks and raccoons are attributed to 42% of
these 55,000 deaths.

Note: Philippines has a very high rate of post-exposure prophylactic

treatments.

Rabies Virology
 Rabies genome is a single, negatively stranded RNA
molecule
 it is bullet-shaped
 Weighs 4.6 x 10 k Dalton
 These viruses are enveloped
Note: There is absence of Rabies in Australia because they are very  Genetic information is packaged as a ribonucleoprotein
vigilant in their anti-rabies drive. complex - RNA is tightly bound by the viral nucleoprotein

Philippines:
 300 to 400 people die from rabies infection each year (2006
report presented by the Department of Agriculture (Bureau
of Animal Industry) Electron micrograph of the rabies virus
 San Lazaro Hospital:  All transcription and replication events take place in the
 90 percent of human rabies cases are due to dog cytoplasm inside a specialized virus factory - the Negri
bites, majority of which are from pets body
Note: Most of the patients are brought to two referral centers for
rabies: San Lazaro hospital and Research Institute for Tropical
Medicine.

Negri bodies
◦ 2–10 µm
◦ typical in a rabies infection and thus have been used as
definite histological proof
◦ Before 1958, it was used as a definitive histological proof
that the patient is a rabies patient.
6|J K C P a l o m a r e s

The virulence factors for the rabies virus include the G protein,
glycoprotein, and cytopathic effects associated with the disease.
Note: Patients exhibit different manifestations of rabies and it would
depend on the virulence factor present in that virus that was able to
enter the patient’s system. Cytopathic effect means that it is trying to
destroy the cell. Degree of severity of the disease depends on the
virulence factors.
Transmission:
• Virus enters body via infected bite
• Some patients may not have visible bites. It can
also be abrasions which can also be a way for the
virus to get inside the body
• Spreads from inoculum site to the spinal cord and brain
• It has a retrograde movement towards the spinal
cord and eventually the brain
• The distribution of rabies virus would be in a
centripetal distribution (from periphery going to
the brain and spinal cord)
• Replication in the brain then travels to parts of the body
– salivary glands, corneal epithelial cells
• It will then have a centrifugal distribution and go
to the salivary glands and other parts of the body
near the brain.
High concentrations of virus in saliva:
a. viral shedding from sensory nerve endings in the oral
mucosa
b. reflects viral replication in the salivary glands
Note: The salivary glands have the most number of viruses in the
body.
Mechanisms for damage to the CNS
 Obscure
 Pathologic evidence of neuronal necrosis is minimal or
absent
 no necrosis or brain damage upon autopsy
 there is no destruction of the brain tissue
 Interferes with neurotransmission and endogenous opioid
system
 Also capable of inducing apoptosis in T lymphocytes
which may relate to the failure of the immune system to
control the disease
Note: The pathology is more on the damage to T lymphocytes rather
than the brain parenchyma or brain tissue.
PATHOLOGY
 Brain in furious rabies usually appears unremarkable
grossly except for the vascular congestion
 Microscopic pathology of rabies: encephalitis (brain
swelling) with Negri bodies
 Negri bodies concentrated in hippocampal pyramidal
cells and cerebellar purkinje cells and less frequently in
cortical neurons
 The concentration of negri bodies is found in the
cerebellar purkinje cells and in the hippocampla
pyramidal cells
 Also found in the heart of some patients via spread from the
nervous system
Note: The most common cause of death in patients with rabies is
myocardiopathy because the negri bodies are able to travel to the
patient’s heart tissue.
Direct Fluorescent Antibody test
 Standard diagnostic method for Rabies
 Test focuses on brain and spinal cord samples for
presence of rabies virus proteins (antigen)
 Infected tissues appear green-yellow under a fluorescence
microscope
Note: This test replaced the identification of negri bodies as a
diagnostic method for rabies.
IMMUNE RESPONSE
 One study suggests that the virus may persist in
macrophages and emerge later to produce the disease.
 This may explain some cases with very long incubation
periods or there may be other tissue locations in which viral
sequestration occurs
 Responsible for the furious and dumb presentation of the
disease
Note: All patients with rabies die. Vaccination and post-exposure
prophylaxis decreases this risk.
CLINICAL MANIFESTATIONS
 Multiple bites more likely to transmit the disease than a
single bite.
 The higher the chance of acquiring the disease
 The shorter the duration of the disease between
the time of exposure and time of death.
 A more aggressive management is given in
patients with multiple bites
 Location of the bite
 bites on the face are more likely to results in earlier
manifestations of the disease than those on the
lower extremities.
 The nearer the location of the bite to the CNS, the
faster the disease progression.
Animals Humans
7|J K C P a l o m a r e s
 may appear sick, crazed, or pain, tingling, or itching at bite o spinal cord and brain stem bear the brunt
vicious site (paresthesia at the point of
entry) Note: the patient will not manifest with aerophobia, agitation, or
may also appear overly hydrophobia. The patient will just manifest with quadriparesis or the
friendly, docile, or confused non-specific: patient sleeps most of the time.
◦ early: fever, chills,
Death fatigue, muscle aches Two manifestations of rabies in acute neurologic phase:
◦ Late: high fever, - hydrophobia
agitation, confusion, o the patient reacts when exposed to water
extreme hydrophobia - aerophobia
and aerophobia
HYDROPHOBIA in Rabies cases
Death  represents an exaggerated irritant reflex of the respiratory
tract
Note: There is a change in the behavior of the animal.  Disturbance in the act of swallowing liquids, discomfort
in the throat, occasional sense of choking
Rabies is preventable through vaccination!  attempts to drink causes spasm in the pharynx which
increases in the course of a few hours, and spreads to the
Five stages of the disease: muscle of respiration
I. Incubation period  Mere sight of water or sound of dropping water will
◦ 20-90 days cause the attack.
• Sometimes even more (up to 2 years)  There is already phobia of water because of the
previous effects caused by drinking
◦ Virus remains at the site
 Visual impressions may also cause the attack like
◦ No symptoms except those related to wound
reflection from a looking glass or even a strong light.
healing
• Tingling Hydrophobia
• Burning sensation ◦ Mental derangement is most intense during the paroxysms
• Wound is already undergoing fibrosis of spasms and patients may spit their saliva and often
◦ VACCINATE attempts to bite with his teeth while making strange sounds
resembling a barking dog.
Note: IP is the time when the patient is exposed to the rabies virus
until the clinical manifestations appear. The best time to vaccinate the PARALYTIC RABIES
patient is during the incubation period.  Resembles an ascending kind of paresis: Guillain-Barre
or symmetric quadriparesis.
II. Prodrome  Guillain-Barre has an ascending type of paralysis
◦ 2 – 10 days  If the patient is showing manifestations of
◦ Virus reaches the spinal cord ascending paralysis think of either Guillain-Barre
◦ Virus moves from the point of entry into syndrome or rabies of the dumb type.
the spinal cord  Weakness severe in the extremities where the virus was
◦ Pain or itching at the bite site because of introduced.
ganglioneuritis  Meningeal signs: headache, stiff neck prominent
despite a normal sensorium as the disease progresses.
III. Acute neurologic phases:
- Divided into two: Note: This is seen in patients who have rabies but only in 20% of the
a. FURIOUS ( ENCEPHALITIC) time.
o 80 %
o Clinical manifestations seen: IV. Coma
▪ Hydrophobia ◦ 4 – 10 days
▪ Delirium ◦ (+) complications
▪ Agitation
▪ Aerophobia Note: When the patient is already in a comatose state, only supportive
or palliative treatment can be given (prevent bed sores, intubate,
Note: Most of the time, what you will see would be patients that are feeding tube). Once this stage is reached by the patient, the next stage
manifesting with the furious type of rabies (80% of cases). This is the will be death.
most common type of acute neurologic phase of rabies.

b. PARALYTIC ( DUMB ) V. Death

o 20 % ◦ Myocarditis
o paralysis of the bitten area ◦ Cardiac arrhythmia
o have little clinical evidence of cerebral ◦ CHF
involvement
8|J K C P a l o m a r e s
 : (-) signs and symptoms of rabies
Note: The most common cause of death in patients with rabies is when
the virus travels to the heart causing arrhythmias, myocarditis, and Category III
congestive heart failure secondary to myocarditis.  Category II head and neck
 Transdermal bites
PREVENTION:  Scratches or abrasions with spontaneous bleeding
 Pre – exposure prophylaxis  Licks on broken skin
 High risk of exposure  Exposure through bites, mucous membranes or open
 3 IM OR intra- dermal injections skin lesions with body fluids splattering and mouth to
 Schedule: mouth resucitation
 Day 0  The mucous membrane transmission of the virus
 Day 7 is very fast because the mucous membrane
 Day 21 or 28 absorbability is quite faster compared to the skin.
 sufficient  Handling of infected carcass or ingestion of raw infected
 Booster doses every 2-3 years meat
 Depends on the risk of the patient in developing
rabies Category III Management
1. Wash with soap and water
Note: Pre-exposure prophylaxis should be given to veterinarians, vet 2. Start vaccine and RIG
med students, animal breeders, pet trainers, works in a city pound, and a. complete until day 28/30:
forestry workers. These are the people who are at high risk for - (+) rabies
exposure. - Animal cannot be observed for 14 days
- Animal killed without testing
Pre – exposure series of three shots: - (+) signs and symptoms
 IM on the deltoid:
◦ PVRV (Purified Vero cell rabies vaccine) – 0.5 ml Omit day 28/30:
◦ PCECV (purified chick embryo cell vaccine) – 1.0  A. animal is alive and healthy after observation period
ml  B. animal died of other causes
 ID on the other deltoid (more painful because it is more
superficial) Note: There are two types of RIG: Human RIG and Equine RIG. ERIG
◦ PVRV or PCECV – 0.1 ml has a lot of hypersensitivity reactions. It is quite cheaper compared to
HRIG. Both have the same efficacy.
Categories of rabies exposure and management:
Locally available rabies vaccines:
Category I
a. touching or feeding and animal
b. intact skin licked
c. casual contact
d. shared eating or drinking utensils

1. Wash with soap and water

2. No vaccine or RIG
3. High risk persons: pre – exposure prophylaxis
- HIV patients

Category II
 Minor scratches or abrasions - no bleeding
 Minor scratches or abrasions induced to bleed
 Nibbling of uncovered skin
Recommended regimen of ID
 Wash with soap and water – reduce virus load by 15%  Recommended for trained health facilities
 Start vaccine ASAP:  Days 0, 3, 7, 28/30
◦ Complete until day 28/30:
 Laboratory proven (+) Delay D3:
 Killed without testing ◦ 1-2 days – give D3 and follow original schedule
 Animal: (+) s/sx of rabies ◦ 3-4 days – give D3 adjust succeeding doses
(-) available for observation ◦ > 4 days – restart regimen
Omit 28/30 dose:
◦ animal: alive after 14 days Delay D7:
◦ animal: died of other causes ◦ < 7 days – give D7 and follow original schedule
: FAT (-) ◦ 7 – 14 days – repeat D3 and revise schedule

9|J K C P a l o m a r e s
 ◦ > 14 days – restart regimen

Note: At D7, the antibodies are already forming.

Locally available RIG:

Passive immunization
 HRIG, ERIG, (Fab’)2
 Infiltrate around the wound
 Anterolateral thigh - use another needle
 Preferred HRIG:
◦ Hypersensitivity to equine
◦ Severe category III head, neck, face
◦ Symptomatic HIV
◦ Newborns of pregnant rabid mother
◦ More expensive

Note: Passive immunization is when you give the immunoglobulin

itself. You do not wait for the body to form antibodies. Infiltrate the
wound + anterolateral thigh.

Case: Patient with bite on the right hand. Infiltrate the wound on the
right hand and give HRIG on the contralateral thigh (left anterolateral
thigh).

TREATMENT
 None - once symptoms have started
 ULTIMATE COURSE : DEATH

TUBERCULOSIS

Today’s focus:
• To understand tuberculosis through an internist’s point of
view.

10 | J K C P a l o m a r e s
 • To learn the current situation of tuberculosis in the
Philippines and the world.
• To learn the latest classification of tuberculosis being utilized
in the Philippines.
• To learn the basic diagnostic examinations in tuberculosis
and their interpretation.
• To know the treatment regimen given to the different
classifications of tuberculosis.
Tuberculosis
• One of the oldest diseases (70,000 years)
• Usually affects the lungs
• Curable in almost all cases
• Case fatality rate as high as 65% in untreated cases
• Robert Koch – German physician that documented and
officially identified tuberculosis. He is the father of
bacteriology. He conducted a lot of studies in cholera and
tuberculosis.
• 1882 – he was able to show samples of TB from guinea pigs
and dead tissues
• Mycobacterium tuberculosis
The mycobacterium complex is composed of eight related species.
The more important of these are:
Group of closely related species:
– M. africanum
• Still exists in some parts of Africa
– M. microti
• Also called as the vole bacilli
• Still present in a small population in the
African continent
– M. bovis
• Used to affect patients drinking raw and
unpasteurized milk
• It usually affect cows
• Importance: this is where the strain of
the BCG bacilli came from.
Mycobacterium tuberculosis
- In the Philippines, the tuberculosis ranks among the top 10
killers of Filipinos.
- Few of the problems that we have are: poverty, inequity
and conflict, suboptimal health services, and the increasing
trend of HIV infection.
- Poverty is a very important factor for the spread of
tuberculosis because the management of TB requires at
least 6 months of treatment which requires a lot of funds.
The cases of TB are greatest in areas reeked with conflict
because of the poor delivery of basic health services.
Country profile of Tuberculosis in the Philippines
- Most cases of TB are in the NCR and provinces of Mindanao
- Increased case notification rates.
- Expanded initiatives and more community task forces
involvement.
- Quality of treatment continues to improve.
- Success rates for new smear positive cases above target for
the past 7 years.
- Better management of MDR TB.
- Ranks number 9 in all forms of incident cases (2006).
Global statistics of TB
- In 2012, 8.6 million new cases of TB
- 1.3 million deaths in 2013.
- 1/8 of patients will die of the complications of TB
- 2012 – 170,000 deaths from MDR TB
- 450,000 new cases of MDR TB in the world
- Cases of TB that are very hard to treat that cannot be
managed by the conventional first line TB drugs
- 65% of TB cases are documented or notified because most
patients do not go to physicians and get treated.
Epidemiologic Burden
• Incidence cases (all forms in 100, 000) – 287
• Prevalence rate – 432/ 100, 000
• Mortality (all forms) – 45/ 100, 000
• MDR TB (new) – 4/ 100, 000
• MDR TB (previously treated) – 21/ 100, 000
WHO Report 2008. Global TB Program
Surveillance and DOTS notification:
• Notification rate – 171/ 100, 000
• DOTS treatment success – 89/ 100, 000
• WHO Report 2008. Global TB Program
Overview:
• As an AIDS related opportunistic infection, TB is associated
with HIV infections
• Dual infections are frequently noted.
• South Africa, India, Nigeria- highest incidence.
• Persons with AIDS are 20 -40 times more likely to develop
active PTB compared with immuno-competent persons.
TB is most common in this set of patients in terms of age as a
demographic?
• Continents that are highly affected by tuberculosis in
whatever form.
• Africa, West Pacific, and Eastern Europe.
• Limited resources, HIV infection, MDR TB.
• MDR TB
• Resistance to the 2 most effective first line drugs. Which are
. . . ??? Question.
• Success rate of treatment is only 60% compared to 85% in
those with drug susceptible TB.
• Extensively drug resistant TB (XDR TB)
• Resistant to INH, Rifampicin, and second line drugs.
• Approximately 1 in 13 M. tuberculosis isolates shows a form
of drug resistance.
• MDR TB and XDR TB
• Produce fulminant disease
• Fatal outcome
• Highly infectious with conversion rates up to 50% in exposed
health care workers.
WHO strategy
A global pandemic developed in the 1980s and early 1990s.
WHO Goal:
• Identify 70% of the world’s TB cases
• Completely treat at least 85 % of the cases by the year 2000.
11 | J K C P a l o m a r e s
 • Development of major surveillance programs and the birth • Mortality and Morbidity
of the DOT. • Fatal disease if untreated.
• DOT • 1/3 die within the first year of diagnosis.
• Requires a third party to witness compliance with • ½ die after the first year.
pharmacotherapy.
• With world – wide efforts, global detection of smear positive Pathogenesis:
cases rose from 11% (1991) to 45% (2003). • Inhalation of droplet nuclei is the first stage.
• 71 – 89 % of the cases underwent complete treatment. • Most are expelled by the body’s defense systems in the
Etiology upper airways. 10% reach the lower airways.
• Slow growing, facultative, obligate aerobe and intracellular. • In the alveoli….
• Grows in parallel groups called cords • Deactivated macrophages phagocytize the bacilli.
• Retains many stains after decoloration with acid – alcohol. • Bacilli attach to the macrophage cell surface molecules like:
• Aerobic, non – spore-forming, non- motile, curved rods. • Complement receptors, mannose receptors, type A
• Humans are the only known reservoir. scavenger receptors, and Ig GFcgamma.
• Cell walls contain mycolic acid rich long chain glycolipids • Once a phagosome forms, the bacilli survives because of
and phospholipoglycans (mycosides) that protect the it from reduced acidification.
lysosomal attack. • Replication begins within the phagosome until ruptures and
• Highly antigenic and they promote a non – specific response releases its bacillary load.
initially. • Genes which give the bacilli virulence:
• katG gene – encodes the catalase/ peroxidase enzyme to
Transmission: protect it from oxidative stress.
• Droplet nuclei are aerosolized by coughing (300, 000 nuclei • rpoV gene – initiates transcription of several genes.
per cough), talking, and sneezing. • Erp gene – protein required for multiplication.
• Droplets dry rapidly but the smallest ones may remain in air • Beijing/ W gene – higher mortality rates and chances of
for several hours and reach the terminal airways. developing MDR TB.
Determinants of transmission: • Innate resistance to TB
• Intimacy and duration of contact with an infectious patient. • NRAMP 1 (natural resistance associated macrophage
• The level of infectiousness of the patient. protein) encodes to chromosome 2.
• sputum smear positives are most likely to transmit the
disease. Clinical manifestations:
• Shared environment. Primary disease:
• Crowding in poorly ventilated rooms. • Children usually affected
• Most infectious patients are: • Middle and lower lung zones.
• (+) cavitary lesions. • Accompanied by hilar or paratracheal lymphadenopathy.
• Sputum containing a heavy load of bacteria. • Ghon complex – spontaneously healed lesion
• PTB with laryngeal involvement. • Pleural effusion may be present especially in the immuno-
compromised adults and children.
Determinants of disease: • Secondary, adult type, post primary tuberculosis
• Innate immunologic and non - immunologic defenses and • Results from endogenous re - infection from a latent
CMI. infection.
• Classification of clinical illness: • Apical and posterior segments of the upper lobes. May also
• Primary tuberculosis. involve the upper segments of the lower lobes.
• Directly follows an infection. • Clinical manifestations
• Children up to 4 years of age. (Post – Primary TB):
• Immuno - compromised patients. • Early non – specific symptoms are:
• Low level of transmission. • Fever and night sweats.
• If acquired during adulthood, better immune system to • Weight loss
contain it. • Anorexia
• Usual course from infection to disease is within two years. • Weakness
• Secondary or Post Primary Infection • Cough – majority. Starts as non – productive to becoming
• More infectious because of the formation of cavitary lesions. blood tinged.
• 10% of infected patients will develop active PTB eventually. • Rasmussen’s aneurysm
• Age is an important determinant: • Other features:
• Late adolescence and young adults • Crackles in the upper chest.
• Women are more affected in this age group. Men are • Mild anemia.
affected more in older age groups. Reason (?). • Leukocytosis.
Elderly • Hyponatremia because of SIADH.
• Risk is higher because of decreasing immunity and the • Fever – 80% of cases.
presence of other diseases (co – morbidity). • Intermittent
12 | J K C P a l o m a r e s
 • Low grade • Spine (40%)
• Chest X ray – Pott’s disease tuberculous spondylitis.
• Extra - pulmonary TB • Lower thoracic spine – children
• Lymphnodes • Upper lumbar spine - adults
• Pleura • Hips
• Genito – urinary tract • knees
• Bones and joints Diagnostic modality:
• Meninges • CT or MRI of the spine.
• Peritoneum • Bone biopsy.
• Pericardium • Aspiration of the abscess.
• Tuberculous lymphadenitis Diagnosis of TB:
o Most common. • AFB smear – easily done
o Around 40 % of cases. • Positive in 40% of the cases.
o Especially noted in HIV patients. • Rapid result
o Painless swelling posterior cervical and • Stains used are the Kinyoun or Ziehl – Neelsen dyes or the
supraclavicular (scrofula). auramine – rhodamine stains.
o Usually associated with pulmonary TB. • specimens: 1 spot collection, 2nd morning collection, 3rd
spot collection
Diagnosis: Mycobacterial Culture
• Fine needle aspiration or excision biopsy. • Definitive diagnosis because it isolates the bacilli.
• AFB positive in 50 %. • 4 – 8 weeks required to release the result.
• Cultures are positive in 80%. • Do also drug susceptibility testing.
• Histology: granulomatous lesion. Treatment:
• Pleural TB Two aims:
• 20% of extra - pulmonary cases. 1. interrupt TB transmission by making patients non
infectious
2. prevent morbidity and death.

Results from: • TB treatment was improved in the 1940s. Why?

• Contiguous spread of parenchymal inflammation • What drug which was discovered in the 1970s heralded the
• Actual penetration of tubercle bacilli into the pleural space. advent of short course (<12 months) TB treatment?
• What drug for the treatment of tuberculosis can only be used
PE findings for a maximum of two months?
• Dullness to percussion and absence of breath sounds in the
involved areas. Chemotherapy is the only way to stop drug transmission.
• CXR – pleural effusion sometimes with the parenchymal Reasons for not being cured:
lung lesion. Stop taking or irregular intake.
• Thoracentesis to determine the effusion. Long duration of treatment makes the patient remiss in taking the drug.
• Pleural fluid analysis:
• Straw colored but may be reddish (Blood). These will eventually lead to chronic infections, drug resistance or
• Exudate with a high protein content > 50% of that to the death.
serum content. Four major drugs as first line therapy:
• Normal to low glucose count. • INH
• pH of 7.3 usually. • Rifampicin
• Detectable leucocytes • Pyrazinamide
• Neutrophiles in the early stage. • Ethambutol
• Mononuclear cells in the later stage.
o Peak serum levels in 2 – 4 hours and elimination
• Genito – Urinary Tuberculosis within 24 hours.
• Accounts for about 15% of extra – pulmonary TB. o Four first line drugs:
• Any portion of the GUT may be involved. o Bactericidal (ability to reduce the number of
• Urinalysis: pyuria and hematuria with a culture negative infectious organisms and make the non –
result. infectious)and
• Females > males o sterilizing (ability to kill all bacilli and sterilize the
• Diagnosis is through culture for MTB of three early morning tissues)properties.
urine samples.
• TB of the Bones and Joints Recommended dose:
• Due to reactivation of hematogenous bacilli or spread from • INH – 5 mg/kg BW (maximum of 300 mgs per day)
adjacent para - vertebral lymph nodes. • RPZ – 10 mgs/ kg BW (maximum of 600 mgs per day)
Joints most affected are: • EMB – 15 – 20 mgs/ kg BW
13 | J K C P a l o m a r e s
 • PZA – 20 – 25 mgs/ kg BW (maximum of 2 grams
Pyrazinamide
How do you approach the treatment of a patient with PTB? • Pyrazine analog of nicotinamide.
Initial empiric therapy: • Either bacterisostatic or bacericidal against the bacillus
Four drug regimen: depending on the concentration of drug attained at the site
INH, RPZ, PZA or Streptomycin. of the infection.
Once the TB isolate is known, the fourth drug can be discontinued. • MOA is unknown.

Guide in managing drug side effects: Ethambutol

Minor side effects – encourage patient to continue taking the
medicines
• Rifampicin – gastrointestinal intolerance- give medication
at bedtime.
• Mild skin reactions – any kind of drugs – give anti-
histamines.
• Rifampicin – orange or red urine – reassure the patient.
Drug side effects….
• Streptomycin – pain at the injection site – apply warm
compress or rotate the injection sites.
• Peripheral neuropathy – INH – give pyridoxine (Vit. B6).
• PZA - Arthralgia due to hyperuricemia – give NSAIDs.
• Flu like symptoms – Rifampicin - antipyretics
• Inhibits the synthesis of 1 or more metabolites of the bacilli
causing cell death.
• No cross resistance.
• Mycobacterial resistance is frequent with previous therapy.
• Usually used with naïve second line drugs.
• Food does not alter its absorption.
Streptomycin
• Given when less potentially hazardous drugs are ineffective
or contraindicated.
• Injected IM.
• Identified satellite treatment centers:

Major side effects . . .

Discontinue giving the medicines and refer to a specialty center.
• Severe skin rash due to hypersensitivity – any kind of drugs
especially Streptomycin – discontinue anti – TB drugs and refer.
• Jaundice due to hepatitis – any kind of drugs especially INH,
Rifampicin and PZA – if symptoms subside, resume treatment
and monitor clinically.
• Impaired visual acuity and color vision – optic neuritis –
ethambutol – refer to an ophthalmologist.
• Hearing impairment, tinnitus, dizziness due to damage of the 8th
cranial nerve – streptomycin – discontinue streptomycin.
• Oliguria or albuminuria due to a renal disorder – streptomycin
or RPZ- discontinue.
• Psychosis or convulsion – INH – discontinue.
• Thrombocytopenia, anemia, shock - RPZ - discontinue.

Medications recap:
Three basic principles:
1. any regimen must use multiple drugs which the bacillus is
susceptible to.
2. treatment must be taken regularly.
3. therapy must continue for a period sufficient to resolve
the illness.

• New cases are treated initially with 4 drugs for 2 months.

• Continuation phase must always include INH and RPZ.
• Retreatment cases should initially receive 5 drugs.

INH
• Drug of choice for preventive therapy.
• Primary drug in combination therapy for active TB.
• Peripheral neuropathy – pyridoxine.
Rifampicin
• Must be used with at least another drug.
• Inhibits DNA dependent bacterial RNA polymerase.

14 | J K C P a l o m a r e s