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TUBERCULOSIS

Vanessa Gayle V. Fajura

Alyana Stephanie L. Picardal

BS Pharmacy - 4
TUBERCULOSIS
• is an airborne bacterial infection caused by the
organism Mycobacterium tuberculosis.

• It mainly affect the lungs but can damage any part of the body
such as the kidney, spine, and brain.

• Tuberculosis is spread from person to person through the air.


When a person with TB in their lungs or throat coughs, laughs,
sneezes, sings, or even talks, the germs that cause TB may spread
through the air.
CAUSATIVE ORRGANISM
TB is caused by tubercle bacilli – genus Mycobacterium
(Mycobacterium tuberculosis)

• rod-shaped, non–spore-forming, aerobic bacterium

•Mycobacteria typically measure 0.5 μm by 3 μm, are


classified as acid-fast bacilli .

•Considered an aerobe since it needs oxygen to survive.

•Cell wall is waxy, and contains peptidoglycan and lipids,


long chain alpha-alkyl, beta-hydroxy fatty acid.

•It is not considered gram negative nor gram positive


although it may weakly stain gram positive when gram
stained.
TRANSMISSION
•Spread by small airborne droplets, called
droplet nuclei, generated by the coughing,
sneezing, or talking of a person with
pulmonary or respiratory tract TB during
expiratory efforts

• These minuscule droplets can remain


airborne for minutes to hours after
expectoration.
PATHOPHYSIOLOGY
CLINICAL MANIFESTATIONS
• As the cellular processes occur, tuberculosis may develop
differently in each patient, according to the status of the
patient’s immune system. Stages include latency,
primary progressive disease(active TB)
LATENT TUBERCULOSIS
• In this condition, the person have a TB infection, but the bacteria remain in
their body in an inactive state and cause no symptoms.

• If the immune system later becomes compromised, as it does in many


critically ill patients, the disease can be reactivated, multiply, and cause TB
disease.
• Triggers that activate LTBI

•HIV • Smoking
•Uncontrolled diabetes mellitus •Chemotherapy
• Sepsis renal failure • organ transplantation, and
•Malnutrition • long-term corticosteroid usage
TUBERCULOSIS DISEASE
• The tubercle bacilli overcome the immune system and
multiply, resulting in progression from LTBI to TB
disease.( TB bacteria are active)

• Persons who have TB disease are usually infectious and


may spread the bacteria to other people.
PULMONARY TUBERCULOSIS
• TB disease most commonly affects the lungs; this is referred to as
pulmonary (respiratory) TB.

• Pulmonary TB may arise from exogenous reinfection or endogenous


reactivation of a latent focus remaining from the initial infection.

• Patients with pulmonary TB usually have a cough and an abnormal


chest radiograph, and may be infectious.

• If untreated, about 65% of patients will die within 5 years, the


majority of these within 2 years.
EXTRAPULMONARY
TUBERCULOSIS
• Extrapulmonary(non-respiratory) TB disease
occurs in places other than the lungs, including
the larynx, the lymph nodes, the pleura, the
brain, the kidneys, or the bones and joints.
TUBERCULOUS MENINGITIS.
• When TB occurs in the tissue surrounding the brain or spinal cord, it is
called tuberculous meningitis.

• Tuberculous meningitis is often seen at the base of the brain on imaging


studies.

• Headaches and change in mental status after possible exposure to


tuberculosis or in high risk groups should prompt consideration of this
disease as a differential diagnosis.

• If not treated, tubercular meningitis is fatal in most cases, making rapid


detection of the mycobacteria essential.
MILIARY TUBERCULOSIS
• Another fatal form of extrapulmonary tuberculosis is infection of the
bloodstream by mycobacteria; this form of the disease is called
disseminated or miliary tuberculosis.

• “Miliary” refers to the radiograph appearance of millet seeds scattered


throughout the lung or throughout the body, leading to multiorgan
involvement.

• It is most common in infants and children younger than 5 years of age, and
in severely immunocompromised persons.
RISK GROUPS
 Persons with medical conditions that weaken the immune system
 Persons who have been recently infected with TB bacteria
 Close contacts of patients with TB, especially those with sputum
smear-positive pulmonary disease
 Groups with high rates of TB transmission, such as homeless
persons, injection drug users, and persons with HIV infection
 Persons who work or reside with people who are at high risk for TB
in facilities or institutions such as hospitals, homeless shelters,
correctional facilities, nursing homes, and residential homes for
those with HIV
Impact of HIV Infection
• People with HIV infection have an increased risk of developing TB if exposed to
infection.

• The estimated annual risk of TB in those with HIV infection and TB co-infection is
around 10% as opposed to a 10% lifetime chance in someone infected with TB, but
not HIV.

• Co-infection of M. tb and HIV is a deadly-duet.

• Someone with untreated latent TB infection and HIV infection is much more likely
to develop TB disease during his or her lifetime than someone without HIV
infection.

• Among people with latent TB infection, HIV infection is the strongest known risk
factor for progressing to TB disease.

• A person who has both HIV infection and TB disease has an AIDS-defining
condition.
Drug-resistant TB
• Multidrug-resistant tuberculosis (MDR-TB) caused by bacteria that
do not respond to isoniazid and rifampicin, the 2 most powerful, first-line
anti-TB drugs.
• MDR-TB results from either primary infection with resistant bacteria or
may develop in the course of a patient’s treatment.
• MDR-TB is treatable and curable by using second-line drugs.
• However, second-line treatment options are limited and require extensive
chemotherapy (up to 2 years of treatment) with medicines that are
expensive and toxic.
• Extensively drug-resistant tuberculosis (XDR-TB): caused by
bacteria that are resistant to isoniazid and rifampicin
DIAGNOSIS
The symptoms and signs of TB include:

• Cough for 3 weeks of more / productive cough


• Sputum usually mucopurulent or purulent
• Haemoptysis not always a feature
• Fever associated with night sweats
• Tiredness and fatigue
• Weight loss variable
• Anorexia variable
• Malaise
LABORATORY TEST
• Acid-Fast
Bacillus (AFB) Smear and
Culture Testing
 Sputum Smear Microscopy
 is the simplest and quickest method of detecting
the infectious patient, by looking for acid-fast
bacilli.
 used to detect several different types of acid-fast
bacilli, but it is most commonly used to identify
an active tuberculosis (TB) infection caused by
the most medically important AFB,
Mycobacterium tuberculosis.
 AFB smears must be confirmed with AFB
cultures.
LABORATORY TEST

 Acid-Fast Bacillus Culture


 used to diagnose active M.
tuberculosis infections as well
as infections due to nontuberculous
mycobacteria.
 A positive culture is proof for an infection
with Mycobacterium tuberculosis, so it is
proof that somebody has active TB.
 AFB cultures can also be used to monitor
the effectiveness of treatment and can
help determine when a person is no
longer infectious.
LABORATORY TEST
• Tuberculin testing or Mantoux
test
 0.5 ml of PPD (Purified Protein
Derivative) is injected intradermally on
flexor aspect of fore arm.
 Site is examined after 48-72 hrs.
 Induration of 10 mm or more is
considered positive.
 Positive test leads to red area at
injection site or the presence of firm
bump at the test site.
LABORATORY TEST
• Chest Radiography
 a non-specific diagnostic tool, as TB may
present as virtually any abnormality on
chest radiography.
 has high sensitivity, but limited
specificity for detecting pulmonary TB.
It is therefore especially suitable for TB
screening and triaging.
 Cavitation may be seen, the incidence Chest radiograph showing
cavitation suggestive of
can vary between 10% and 30%. pulmonary TB.
LABORATORY TEST
• Molecular tests for TB (nucleic
acid amplification test or NAAT)
 detect the genetic material of
mycobacteria.
 tests are often used when the AFB
smear is positive or TB is highly
suspected
 Allows for screening common
resistance-causing mutations
 must be confirmed with an AFB
culture.
LABORATORY TEST
• DNA fingerprinting, or strain
typing
 a relatively new laboratory
technique—offers promise as a
powerful aid in the prevention
and control of tuberculosis
(TB).
 is useful in the public health
management of TB.
TREATMENT
• In treating TB, a number of factors are important:
 Choice of drugs
 Length of treatment
 Co-morbidity especially HIV infection, liver and renal diseases
 Adherence to treatment by the patient.

• Two main purposes of TB treatment


• To cure people with TB, provided the bacilli are drug sensitive;
• To control TB, by either preventing the development of infectious
forms or reducing the period of infectivity of people with infectious
disease.
BACTERIAL
CHARACTERISTICS
• Three populations of the M. tuberculosis (MTB)
organism.
 Actively growing extracellular bacilli.
 Slow growing or intermittently growing bacilli
 Slower growing bacilli

• Rifampicin is the only drug that is bactericidal against all three populations.

• Isoniazid, streptomycin and the other aminoglycosides are bactericidal against


extracellular bacilli.

• Pyrazinamide is bactericidal only against intracellular organisms and works well in


an acidic pH.

• Quinolones have the highest bactericidal activity against M. tuberculosis


TREATMENT
• Initial empiric treatment for respiratory and other forms of TB:
1. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol –
initial 2 months (initial phase)
2. Rifampicin and Isoniazid – further 4 months (continuation
phase)
• The purpose of the use of four drugs in the initial phase is to reduce
the bacterial population as rapidly as possible and prevent the
emergence of drug-resistant bacteria.
• Combination tablets can be used to prevent accidental or inadvertent
single drug therapy that may lead to acquired drug resistance within
weeks in active TB.
TREATMENT
• Once the TB isolate is known to be fully susceptible,
Ethambutol or Streptomycin may be discontinued.

• If isolated isoniazid resistance is documented, discontinue


isoniazid and continue treatment with rifampin,
pyrazinamide, and ethambutol for the entire 6 months.

• Therapy must be extended if the patient has cavitary


disease and remains culture-positive after 2 months of
treatment.
FIRST-LINE TREATMENT
Isoniazid (INH)
• Isonicotinic Acid Hydrazide
• Monomethyl Hydrazine (MMH) is its toxic metabolite which causes seizures
• The most active drug used for the treatment of tuberculosis caused by
susceptible strains
• Inhibits synthesis of mycolic cells making it bactericidal
• Enzyme inhibitor
• Should be taken with Vitamin B6 (pyridoxime) since one of its side effects
are peripheral neuropathy
• It is also hepatotoxic
• Dose: 300mg/d
FIRST-LINE TREATMENT
Rifampicin (RIF)
• A semisynthetic derivative of rifamycin which is an antibiotic produced
by Streptomyces meditterranei
• Blocks RNA production by inhibiting DNA dependent RNA polymerase
and is therefore considered a bactericidal
• Must be administered with Isoniazid or other anti-TB drugs to patients
with active tuberculosis to prevent emergence of drug-resistant
mycobacteria
• Good prophylaxis for meningococcal HIB (Haemophylus Influenza Type
B) infections
• When counselling a patient taking Rifampicin, do tell that it is normal
and harmless that the urine, sweat and tears will turn orange in color
• It is also hepatotoxic, and causes red-orange discoloration of body fluids
• Dose: 450mg/kg per day
FIRST-LINE TREATMENT
Ethambutol (Eth)
• Inhibits arabinosyl transferases involved in the
polymerization of arabinoglycan which is an essential
component of mycobacterial cell wall.
• Added if the isolate is resistant to Isoniazid or Rifampicin
or both
• Causes optic neuritis (red-green color blindness)
• Not suitable for developing children
• Dose: 15mg/kg per day
FIRST-LINE TREATMENT
Pyrazinamide (PZA)
• Pyrazinoic acid is the active form
• Disrupts cell membrane synthesis, metabolism and transport
functions
• Important front line drug along Isoniazid and Rifampicin
• Reduses isoniazid and rifampicin to 6 months
• The only TB drug that provokes gout arthritis
• Side effects include hyperuricemia and hepatotoxicity
• Dose: 1.5 -2.0g per day
SECOND LINE TREATMENT

• The alternative drugs are considered only


 in case of resistance to first line agents
 In case of failure of clinical response to conventional
therapy; and
 in case of serious treatment – limiting adverse drug
reaction
SECOND LINE TREATMENT
Streptomycin
• Obtained from Streptomyces

• Aminoglycoside

• Interferes with the transcription of DNA to RNA

• Bacteriostatic

• It is the DOC for tularemia and brucellosis

• It is ototoxic and nephrotoxic

• Can cause 8th cranial damage

• It is mainly used as a second line treatment for tuberculosis

• Dose: 750 mg- 1g per day


SECOND LINE TREATMENT
Ethionamide
• Chemically related to isoniazid
• Blocks the synthesis of mycolic acids
• Poorly water soluble and available only in oral form
• Metabolized by the liver
• Initial dose: 250 mg once daily
• It is also hepatotoxic
SECOND LINE TREATMENT
Capreomycin
 Is
a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus
 (15mg/kg/d)is an important injectable agent for
treatment of drug- resistant tuberculosis
 Nephrotoxic and ototoxic
 Tinnitus, deafness and vestibular blindness may occur
 Dosing is the same as that of streptomycin
SECOND LINE TREATMENT
Cycloserine
 Is an inhibitor of cell wall synthesis
 Dosing in TB is 0.5-1 g/d in two divided oral doses
 Most serious toxic effects are peripheral neuropathy and
CNS dysfunction, including depression and psychotic
reactions
 Pyridoxineshould be given with cycloserine because this
ameliorates neurologic toxicity
SECOND LINE TREATMENT
Aminosalicylic Acid (PAS)
 Is a folate synthesis antagonist that is active against M tuberculosis
 Structurally to p-amino-benzoic acid (PABA) and to the sulfonamides
 Readily absorbed from the gastrointestinal tract
 The dosage is 8-12 g/d orally for adults and 300 mg/kg/d for children
 It is widely distributed in tissues and body fluids except the
cerebrospinal fluid
 High concentrations in the urine will result to crystalluria
SECOND LINE TREATMENT
Aminosalicylic Acid (PAS)
 Gastrointestinal
symptoms are common and may be
diminished by giving the drug with meals and with
antacids
 Peptic ulceration and hemorrhage may occur
 Hypersensitivityreactions manifested by fever, joint
pains, skin rashes, hepatosplenomegaly, hepatitis,
adenopathy and granulocytopenia often occur after 3-8
weeks of PAS therapy
SECOND LINE TREATMENT
Kanamycin & Amikacin
 Aminoglycoside antibiotics
 Kanamycin- used for treatment of tuberculosis caused by
streptomycin-resistant strains.
 Amikacin- has a prevalence of multidrug-resistant
strains also active against atypical mycobacteria
 Kanamycin resistance often indicates resistance to
amikacin as well
SECOND LINE TREATMENT
Fluoroquinolones
 Activity against gram-positive and gram-negative
bacteria
 Ciprofloxacin 750 mg orally twice a day
 Levofloxacin 500-750 mg once a day
 Gatifloxacin

 Moxifloxacin 400 mg once a day


 Inhibits strains of M tuberculosis in vitro
SECOND LINE TREATMENT
Linezolid
 Inhibits strains of M tuberculosis in vitro at concentrations of 4-8 mcg/ml

 Blocks 23s

 achieves good concentrations and it is active in murine models of


tuberculosis

 Used in combination with second and third line drugs for patients with
tuberculosis caused by multidrug-resistant strains

 Adverse effects: bone marrow suppression

irreversible peripheral

optic neuropathy

• Dosage: 600 mg (adult) administered once a day


SECOND LINE TREATMENT
Rifabutin
 Derived from rifamycin and is related to rifampin
 Has a significant activity against M tuberculosis, MAC, and
Mycobacterium fortuitum
 Is a both substrate and inducer of cytochrome P450 enzymes
 Less potent inducer, indicated in treatment of tuberculosis in
patients with a HIV infection who are receiving antiretroviral
therapy with a protease inhibitor or a nonnucleoside reverse
transcriptase inhibitor
 Typical dosage: 300 mg/d
SECOND LINE TREATMENT
Rifapentine
 Is an analog of rifampin
 Active against both M tuberculosis and MAC
 Bacterial RNA polymerase inhibitor
 Potent inducer of cytochrome P450 enzymes
 25-desacetylrifapentine is the microbiologically active metabolite have a
elimination half life of 13 hrs.
 Dosage: 600 mg (10 mg/kg) once or twice weekly
 Should not be used to treat patients with HIV infection because of an
unacceptably high relapse rate with rifampin- resistant organisms.
 Given once weekly for 3 months, is an effective short course treatment for latent
tuberculosis infection
SECOND LINE TREATMENT
Bedaquilline
 A diarylquinoline, is the first drug with a novel mechanism of action
against M tuberculosis to be approved since 1971
 Inhibits adenosine 5’- triphosphate (ATP) synthase in mycobacteria
 Has a vitro activity against both replicating and nonreplicating
bacilli and a bactericidal and sterilizing activity in murine models of
TB
 Mean terminal half life of bedaquilline and its major metabolite (M2)
4-6 times less active in terms of antimycobacterial potency, is
approximately 5.5 months
SECOND LINE TREATMENT
Bedaquilline
 CYP3A4 is the major isoenzyme involved in the metabolism of
bedaquilline
 Bedaquilline in combination with at least three other active
medications can be used for 24 months in patients with laboratory
confirmed pulmonary TB
 Dosage: 400 mg once daily orally for 2 weeks followed by 200 mg
three times a week for 22 weeks taken orally with food to maximize
absorption.
 Associated with hepatotoxicity and cardiac toxicity.
Treatment
Respiratory TB
• Active TB affecting: lungs, pleural cavity, mediastinal lymph nodes, and
larynx

• The standard 6-month regimen is recommended


oAdults not known to be HIV positive
oAdults who are HIV positive
oChildren
TB of peripheral lymph nodes
• 6 months of treatments are just as effective as 9
months for fullysusceptible bacilli
MENINGEAL TB TREATMENT
• Rifampicin and isoniazid for 12 months together with pyrazinamide,
and normally ethambutol, for the first 2 months.

• Ethambutol is used in unconscious patients as a decline in visual


acuity(side effect of ethambutol).

• The use of glucocorticoids is also recommended in the management of


meningeal TB. Consideration should be given to their gradual withdrawal
within 2–3 weeks of initiation
Recommended dose(National Institute for Health and Clinical Excellence,
2006)

 Adults: equivalent to prednisolone 20-40 mg if on rifampicin, otherwise


10-20 mg
 Children: equivalent to prednisolone 1-2mg/kg, maximum 40 mg
BONE AND JOINT TB TREATMENT
• The spine is the most common site for bone TB.
• Isoniazid and Rifampicin for 6 months +
pyrazinamide and ethambutol in the initial
phase (2 months)
• Surgery may be needed to relieve spinal cord
compression or to correct spinal deformities
DISSEMINATED TB TREATMENT
• The standard 6-month regimen containing both
isoniazid and rifampicin, with pyrazinamide and
ethambutol in first 2 months.
• If
there is evidence of CNS involvement,
treatment should be the same as for meningeal
TB.
PERICARDIAL TB TREATMENT
• Thestandard 6-month treatment regimen is
recommended for patients with active pericardial
disease.
• Glucocorticoids should also be prescribed.
 Adults: glucocorticoid equivalent to prednisolone at 60 mg/day

 Children: glucocorticoid equivalent to prednisolone 1-2mg/kg/day


(maximum 40mg/day), with gradual withdrawal of the
glucocorticoid, starting within 2-3 weeks of initiation
TREATMENT OF TB IN SPECIAL
CIRCUMSTANCES
TB in children

• Doses are generally estimated to facilitate prescription of easily


administered volumes of liquid or tablets of appropriate strength.

• Ethambutol should not routinely be used in young children, who would be


unable to report visual disturbances should they occur.

Immunocompromised patients
• Should be treated with normal first-line agents unless multidrug-resistant TB is
suspected

• These patients have a greater risk of relapse and may need to be treated for longer
than the normal 6 months.
TREATMENT OF TB IN
SPECIAL CIRCUMSTANCES
Pregnancy
• Standard therapy should be given, although streptomycin
should not be used as it may be ototoxic to the fetus.
• Pyridoxine (Vitamin B6) supplementation (10-25mg/day)
is recommended for breastfeeding women taking
isoniazid.
• Patient should be warned of the reduced effectiveness of
oral contraceptives in regimens containing rifampicin,
and advised to use other, non-hormonal contraceptives.
TREATMENT OF TB IN
SPECIAL CIRCUMSTANCES
Renal Disease
• May be given isoniazid, rifampicin and pyrazinamide in standard
doses as these drugs are predominantly eliminated by non-renal
routes.
• Ethambutol undergoes extensive renal elimination and therefore
dose reduction is needed.
• Streptomycin must be used with considerable caution to prevent
toxicity and is best avoided in renal failure.
• Rifampicin may be given in standard doses to patient on dialysis.
TREATMENT OF TB IN
SPECIAL CIRCUMSTANCES
Liver disease

• Monitoring of liver enzymes is recommended in px with liver failure or in


alcoholics because rifampicin, isoniazid and pyrazinamide are all potentially
hepatotoxic.

• Increased transaminases occur at the start of anti-tuberculosis treatment


frequently – transient and not a reason for stopping treatment unless frank
jaundice or hepatitis develops

• It is usually possible to restart treatment when transaminases have


returned to pre-treatment levels.
TREATMENT OF TB IN
SPECIAL CIRCUMSTANCES
TB and HIV co-infection

• If patients on anti-tuberculous therapy are started on highly active


antiretroviral therapy (HAART): Antiretrovirals should be chosen to avoid
interaction with TB.

• Chemo-preventive therapy for TB is not recommended in HIV-infected


patients.

• HAART is effective at reducing the incidence of new TB in HIV-infected


people.

Drug-resistant TB

• Treatment has to be individualized, requires a complex regimen involving


the use of multiple reserve drugs.
Chemoprophylaxis
• Important in preventing vulnerable individuals with
LTBI from developing active TB disease.

• Without chemoprophylaxis, 40-50% of infants and 15% of


older children with LTBI will develop active TB disease
in 1-2 years.

• Prophylaxis is usually with isoniazid alone for 6 months


or rifampicin and isoniazid for 3 months.
BCG VACCINE
• BCG, or bacille Calmette-Guerin, is a vaccine for tuberculosis
(TB) disease.
• Contains a live, attenuated strain derived from M. bovis.
• It does not protect against infection, but it prevents the more
serious forms of disease such as military TB and meningeal
TB.
• Most age groups require a Mantoux test prior to being offered
BCG vaccine.
• The BCG vaccine should be considered only for very select
persons who meet specific criteria and in consultation with a
TB expert.
Recommendation for BCG
vaccine:
Children. BCG vaccination should only be considered for children who have a negative
tuberculin skin test and who are continually exposed, and cannot be separated from, adults
who:
• Are untreated or ineffectively treated for TB disease (if the child cannot be given long-term
treatment for infection); or
• Have TB caused by strains resistant to isoniazid and rifampin.

Health Care Workers. BCG vaccination of health care workers should be considered on an
individual basis in settings in which
• A high percentage of TB patients are infected with M. tuberculosis strains resistant to both
isoniazid and rifampin;
• There is ongoing transmission of such drug-resistant M. tuberculosis strains to health care
workers and subsequent infection is likely; or
• Comprehensive TB infection-control precautions have been implemented, but have not been
successful.
CONTRAINDICATIONS
Immunosuppression.

 BCG vaccination should not be given to persons who are immunosuppressed


(e.g., persons who are HIV infected) or who are likely to become
immunocompromised (e.g., persons who are candidates for organ
transplant).

Pregnancy.

 BCG vaccination should not be given during pregnancy. Even though no


harmful effects of BCG vaccination on the fetus have been observed, further
studies are needed to prove its safety.
PATIENT CARE
Directly observed therapy (DOT)
This is the internationally recommended strategy that
has been recognized as a highly efficient and cost-
effective strategy to stop the spread of TB.
Where the patient is observed taking their anti-TB
medication by a health care professional
 Considered where non-adherence to treatment might be
a problem
MONITORING TREATMENT
• Sputum examination and culture are the most
sensitive markers of treatment success from
Pulmonary TB
• If
a patient does not become culture negative, it
may due to drug resistance or non-adherence.
• Goodadherence is essential if treatment is to be
successful and checking can be difficult,
especially when a patient is unwilling to
cooperate.

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