TB (D9)

Tuberculosis and its pharmacotherapy
Ayesha Sana
Lecturer
(Clinical Pharmacy)
CONTENTS
DEFINITION
EPIDIMOLGY
TYPES OF TUBERCULOSIS
ETIOLOGY
TRANSMISSION
INCUBATION PERIOD
RISK FACTOR
PATHOPHYSIOLOGY
CLINICAL FEATURES
DIAGNOSTIC TEST
MANAGEMENT
PATIENT COUNSELING/ ROLE OF PHARMACIST
MONITORING
REFERENCES
01/05/2023 Infectious diseases (TB) 2

DEFINITION
“Tuberculosis (TB) is a communicable, chronic, granulomatous, progressive
infectious disease caused by Mycobacterium. It can produce silent, latent infection as
well as progressive, active disease. It mainly affect the lungs but can also affect other
parts of body.”

EPIDEMOLOGY
4
Across the World:

Each year there are an estimated;
8 million new cases
2-3 million death from the disease
01/05/2023 Infectious diseases (TB)

Epidemiology in Pakistan:
No. of Cases of TB in 2012= 284000
No. of Cases of TB in 2013=300,000
2013 Pakistan is at 4th position regarding the prevalence of

MDR-TB
No. of cases of TB with HIV coinfection is 1500

6
Types of tuberculosis
PRIMARY TB
TB
SECONDARY
TB
01/05/2023 Infectious diseases (TB)

ETIOLOGY
Caused by tubercle bacilli, belongs to the genus Mycobacterium that include;
M. Tuberculosis (98%)
M. bovis
M. africanum

TRANSMISSION
Through exposure to tubercule bacilli in airborne droplet nuclei produce
by person with active pulmonary TB, whose sputum contains a
significant number of organisms (typically enough to render the smear
positive).
Each droplet nuclei contain one to three organisms
During expiratory efforts such as coughing, sneezing.

INCUBATION PERIOD
The incubation period may vary from about two to 12 weeks.

 A person may remain contagious for a long time (as long as viable TB
bacteria are present in sputum).
And can remain contagious until they have been on appropriate
therapy for several weeks.

RISK FACTORS
 HIV patient
 Close contact with TB patient
 Alcoholic and injection drug user
 Diabetes mellitus
 Immunosuppressive treatment
 Malnutrition and sever underweight

PATHOPHYSIOLOGY
A. PRIMARY INFECTION AND PRIMARY TB
M.tuberculosis got entry in the body by any of the following route;
Inhaling air borne particle
Ingestion (swallowing)
Inoculation (puncture wound)

At the alveolar surface, the bacilli that were delivered by the droplet nuclei
These bacilli are then ingested by pulmonary macrophages.
If these macrophages inhibit or kill the bacilli, infection is aborted.
If the macrophages cannot do this, the organisms continue to multiply.
The macrophages eventually rupture, releasing many bacilli
These mycobacteria are then phagocytized by other macrophages.

These mycobacteria are highly antigenic and promote immune response
Cellular immune reaction occur and may accompanied by spread of bacilli

through blood and lymphatic system.
Granulomas are formed by the action of macrophages and activated T-cell
T-cell clumps together and surround the tubercle bacilli
Bacilli grouped in centered of granuloma
Granulomas become avascular and necrotic because of surrounding fibrosis.

PATHOPHYSIOLOGY
Approximately 90% of patient who experience primary disease have no

further clinical manifestation
Approximately 5% of patient (usually children, elderly,
immunocompromised) experience progressive primary infection
(usually the lower lobes) and frequently by dissemination, leading to
meningitis and often to involvement of the upper lobes of lungs as well.

PATHOPHYSIOLOGY
B.SECONDARY/EXTRAPULMONARY/
REACTIVATION TB
 The lungs are the most common site for reactivation.
 For reason that are not entirely known, organisms within
granulomas emerge and begin multiplying extracellular.
 Approximately 10% of patient develop this disease, which arises
subsequent to the hematogenous spread of organism.
 Occasionally , a massive inoculum of organism may be
introduced into the bloodstream , causing widely disseminated
disease and granuloma formation known as Millary TB

The inflammatory response produces caseating granulomas,
eventually will liquefy and spread locally,
leading to the formation of a hole (cavity) in the lungs.
If left untreated, pulmonary TB continue to destroy the lungs,
resulting in hypoxia, respiratory acidosis and eventually death.

CLINICAL PRESENTATION
CLINICAL PRESENTATION OF TB
Signs and Patients typically present with weight loss, fatigue , Hemoptysis, fever,
Symptoms and Frank hemoptysis, drenching, dyspnea, wheezing and chest pain.
Physical Dullness to chest percussion, rates and increased vocal fremitus are

Examination observed frequently on auscultation.
Laboratory Tests Moderate elevations in the white blood cell (WBC) count with a

lymphocyte predominance
Chest Patchy or nodular infiltrates in the apical areas of the upper lobes or
Radiograph the superior segment of the lower lobes. Cavitation that may show air-
fluid levels as the infection progresses

CLINICAL PRESENTATION
Extrapulmonary TB
 Typically present as a slowly progressive decline
in organ
 Patient may have low grade fever and other symptoms.
 Lymphadenitis
 Tuberculous arthritis and osteomyelitis
 Abnormal behavior, headaches or convulsions suggest
tuberculous meningitis
 Involvement of peritoneum, pericardium, larynx and
adrenal gland also occur

DIAGNOSTIC TEST
Symptoms and signs
Radiographic appearance
Tuberculin skin test: using purified protein derivative (PPD)
Microbiological investigation(confirmation)
PCR
MANAGEMENT
DESIRE OUTCOME
1. Rapid identification of a new TB case by collection of appropriate samples for smear
and cultures.
2. Isolation of patient with active disease to prevent spread.
3. Initiation of specific Antituberculosis treatment.
4. Prompt resolution of the signs and symptoms of disease.
5. Achievement of a noninfectious state in the patient, thus ending isolation.
6. Adherence to the treatment regimen by the patient.
7. Cure of the patient as quickly as possible (generally at least 6 months of treatment).
8. Best measure of regimen efficacy.

MANAGEMENT
GENERAL APPROACHES TO TREATMENT OF TB
Drug treatment is the cornerstone of TB management.
Mono- therapy can be used only for infected patients who do not have active TB (latent
infection, as shown by a positive skin test).
Once active disease is present, minimum of two drugs, and generally three or four drugs,
must be used simultaneously.
The duration of treatment depends on the condition of the host, extent of disease, presence
of drug resistance, and tolerance of medications.
The shortest duration of treatment generally is 6 months, and 2 to 3 years of treatment may
be necessary for cases of multidrug-resistant TB (MDR-TB). Because the duration of
treatment is so long, and because many patients feel better after a few weeks of treatment,
careful follow-up is required.
01/05/2023
Directly observed therapy by a healthcare worker is a cost- effective way to ensure
Infectious diseases (TB) 21
MANAGEMENT:
AIMS of Non-pharmacological treatment:
Prevent the spread of TB
Find where TB has already spread using contact investigation
Replenish the weakened (consumptive) patient to a state of

normal weight and well-being.
BCG Vaccination

MANGEMENT:
STANDARD TB TREATMENT REGIMEN

Pharmacological treatment:
1st line drugs 2nd line drugs

Clarithromycin
Isoniazid
Cycloserine
Rifampicin
PASA
Pyrazinamide
Ciprofloxacin
Ethambutol
Streptomycin
Rifabutin
Kanamycin
Streptomycin is no longer considered a first line drug by the ATS, IDSA or CDC.
Other drugs: Pyridoxine (for neuropathies and to person at high risk of vt B6 deficiency)

MANAGEMENT:
 Phases Of Treatment: Standard treatment is divided into:
A. Initial or bactericidal phase

The majority of the tubercule bacilli are killed, symptoms resolve and usually
the patient become noninfectious. Using 4 drug for 2 months (Isonaizid,
rifampicin, pyrazinamide and ethambutol)
B. Continuation or sterilization phase

It is required to eliminate persisting mycobacteria and prevent relapse.
Using atleast 2 drug for 4 months (isoniazid and rifampicin). Longer
treatment is necessary for meningitis, direct spinal cord involvement
and for resistance organism which may also require modification of the
regimen.
MANAGEMEN
T:
Recommended dosage:
 Unsupervised treatment or daily dosing
 Supervised treatment (3 times a week); fully supervised (directly observed therapy
DOT) for non-compliant patient.
Recommended dosage for initial treatment of Tuberculosis in adults
Dosage
Drug Daily Dose Thrice Weekly Dose
Isonaizid 5mg/kg, max 300mg 10mg/kg, max 900mg
Rifampicin 10mg/kg, max 600mg 10mg/kg, max 600mg
Ethambutol 15mg/kg 30mg/kg
Pyrazinamide 20-25mg/kg, max 2g 35mg/kg, max 3g
MANAGEMENT
The duration of treatment with individual drugs varies by regimen.
In certain setting streptomycin (15mg/kg daly, with a maximum dose of 1g; or 25-30mg/kg
thrice weekly, with a maximum dose of 1.5g) can replace ethambutol in the initial phase of
treatment.
TWICE WEEKLY DOSE:
Dosage for twice weekly administration are the same for isoniazid and rifampicin but are
higher for pyrazinamide (50mg/kg, with a maximum of 4g) and ethambutol (40-50mg/day)
NOTE: A twice-weekly regimen after 2-8 weeks of daily therapy during the initial phase
is sometimes used although it is not recommended by the WHO.
DOSAGE FOR CHILDREN:
Dosage for children are similar, except that some authorities recommended higher doses of
isoniazid (10-15 mg/kg daily; 20-30 mg/kg intermittent and rifampicin 10-20 mg/kg)

MANAGEMENT
WELL KNOWN BRANDS
®MYRIN-P
® MYRIN
® RIMACTAL-INH
® PIZA-CIBA

MANAGEMENT:
Tuberculosis Treatment Regimen in Special Situation
Situation Months of Comments
treatment
Cavitary CXR 9 If initially CXR shows cavitation and sputum remain culture positive after 2 months of TB treatment, the
and Culture continuation phase (INH and RIF) should be an additional 3 month (lasting 7 months instead of 4 months)
After 2 months for a total of 9 month of treatment.
Culture 4 For persons with suspected pulmonary TB who have negative culture but clinical or radiographic
negative improvement the continuation phase can be shortened to 2 month for a total of 4 months of treatment.
Exception: If HIV Seropositive or cavitation on CXR, then treat for 6 month total.
Bone/ Joint TB 9 Extend standard therapy to a total of 9 months.

CNS TB 9-12 For TB meningitis, extend standard therapy for a total of 9 to 12 months. Adjunction dexamethasone use
recommended. Consult a TB expert.
Pregnancy 9 Treat without delay. Start with INH, RIF, and EMB (not PZA).Discontinue EMB once INH and RIF
susceptibility has been demonstrated. Continue INH and RIF.
Give equivalent of pyridoxine 50 mg/day( unless already taking the equivalent in a prenatal vitamin) using
INH due to isoniazid induced hepatotoxicity.
Streptomycin should not be given in pregnancy.
MANAGEMENT
:
treatment
HIV Co- Usually 6 CD4+ T Cell <100/mm3: Due to increased risk of acquired Rifampicin resistance, give
Infection daily or thrice (3x) weekly. CD4+ T Cells≥100/mm3: Standard dosing.
Anti-retroviral therapy: If taking anti-retroviral at TB diagnosis, continue them, When
anti-retroviral are medically indicated, their initiation generally. Should be postponed
for 2 to 3 months after start of TB treatment. Patient on protease inhibitors and non-
nucleoside inhibitors with Rifampicin.

Liver disease 18 Antituberculer drugs that rely on hepatic clearance for most of their elimination include
isoniazid, rifampicin, ethionamide and p-amino salicylic acid. For some patient with
drugs susceptible TB, a “live-sparing” regimen of streptomycin, levofloxacin and
ethambutol may be used , at least temporarily because this regimen requires 18 or
more month of treatment to be successful, patients usually are switched to isoniazid
and rifampicin

MANAGEMENT:
treatment
Renal 6 If creatinine clearance <50 or on renal dialysis, then decrease dose to 50%
Disease If on hemodialysis, no supplement because plasma rifampicin concentration
are not significantly affected by hemodialysis or peritoneal dialysis
Pyrazinamide and ethambutol typically require a reduction in dosing
frequency from daily to three times weekly.
2nd line drugs need dose adjustment in renal failure because they are
eliminated through kidney.
Children 9 TB in children may be treated with regimen similar to those used in adults,
although some physician still prefer to extend treatment to 9 month. Pediatric
dose of isoniazid and rifampicin on a milligram per kilogram basis are higher
than those used in adults.
MANAGEMENT
Latent Tuberculosis Infection (LTBI)
LTBI is asymptomatic infection with M.tuberculosis; usually defined as positive
tuberculin test (TST)
LTBI is treated to decrease the risk of progression to active TB/preventing active disease
This intervention is also called preventing chemotherapy or chemoprophylaxis

MANAGEMENT
DRUG RESISTANCE TB
1. MDR-TB
2. XDR-TB
Patients who have received prior therapy for TB
Patients from areas with a high prevalence of resistance (NewYork City, Mexico,
Southeast Asia, the Baltic countries, and the former Soviet states)
Patients who are homeless, institutionalized, intravenous drug abusers, or infected with
HIV
Patients who still have acid-fast bacilli-positive sputum smears after 1 to 2 months of
therapy
Patients who still have positive cultures after 2 to 4 months of therapy
 Patients who fail treatment or relapse after treatment Patients known to be exposed to
MDR-TB cases
ROLE OF PHARMACIST/
PATIENT EDUCATION:
Explain the importance of therapy.
Instruct patient to take drug on empty stomach, 1hr before meal.
Advise patient to avoid alcohol.
Instruct patient to report following symptoms to physician: Weakness, fatigue, loss of
appetite, nausea and vomiting ; yellowing of skin colour; darkening of urine; numbness
in hands or feet.
Advise patient to return for laboratory follow up.
RIF: inform patient that body fluid may turn red-orange in colour and that soft lense
may become permanently stained. Advise patient to wear glaases during course of
therapy.
You will need to have frequent ophthalmic exams
MONITORING OF THERAPY:
• LFTs in case of isoniazid, • Opthalmic
rifampicin usage. examination should be
done after treatment
with antituberculous
Sputum drugs
Compliance
examination
monitoring.
and culture
Drug
resistance
and non- RIF: The red
adherence; colourizing
positive
• Renal failure should be checked before
culture
treatment with antituberculous drugs • Baseline serum uric
acid test for patient on
pyrazinamide
MONITORING OF RESPONSE:
Monitoring Parameter
Comments
Chest After initial CXR, only repeat If clinically indicated. With suspected culture
Radiographs
negative TB, perform a CXR at 2 month to evaluate for CXR improvement.
For pulmonary cases, a CXR should be obtained when treatment is

completed.
Sputum Obtain 3 early morning sputum monthly until culture conversion is
documented. Extend treatment if culture conversion occur after 2 month of
treatment, then obtain sputum.

Vital Signs Weight and treatment are often a critical measure of treatment response.
TB Signs and Check for cough, hemoptysis, chest pain, fever, night sweats, fatigue, and
symptoms
malaise.


MONITORING OF ADR :
1 Blood Work Baseline liver function test, uric acid and complete blood count including
platelets. Monthly liver function tests should be dones only for those with:
a) HIV infection
b) History of heavy alcohol use, liver disease or chronic hepatitis
c) LFTs in case of isoniazid, rifampicin be hepatotoxic.
d) Streptomycin or ethambutol should preferably be avoided in patient with
renal impairment, but if used, the dose should be reduced and plasma-drug
concentration monitored.
e) Serum uric acid: Patient with TB who are receiving pyrazinamide should
undergo baseline and periodic serum uric acid assessment.
2 Vision While on ethambutol, check visual acuity (snellen) and color vision (lsihara). If
on EMB greater than 3 months, evaluation by an ophthalmologist is required.
3 Signs and Symptoms Check for nausea, vomiting, abdominal pain, decreased appetite, jaundice, dark
urine, rash /itching, joint and tingling extremities.

RESEARCH

RECENT WORK ON TB VACCINATION
 Sixteen different TB vaccine candidates are currently in clinical trials, with a
handful approaching or currently in proof-of concept (phase IIb) studies in
the field, and many more in preclinical development. These vaccine
candidates include five which are based on whole cell mycobacteria, and the
remainder are various sub-unit based approaches in which M.tb antigens are
expressed as recombinant proteins that are either formulated with adjuvants
or presented in recombinant viral vectors.
 Further boosting by the modified-vaccinia-ankara (MVA)85A vaccine failed

to enhance efficacy in a clinical trial.
Strategies Of Vaccine Development
Due to the complex nature of Mycobacterium tuberculosis (M.tb) and its
pathology within the human host, multiple vaccine development strategies are
being pursued:
Prevention of infection: vaccines that can be given prior to M.tb exposure, in
order to prevent initial infection and therefore disease
Prevention of disease: vaccines that can be administered after exposure to
M.tb, to people who are infected but may be asymptomatic and at risk of
developing disease in the future. This type of vaccine would protect against
manifestation of active disease and therefore reduce transmission.
Prevention of recurrence: vaccines that can be administered after infection
and treatment of M.tb disease, to prevent reactivation and subsequent
transmission
TREATMENT OF MDR-TB
 Bedaquiline is the first drug in a new class of anti-tb medications to be
approved in more than 40 years by the US, Food and drug administration
(FDA).
 It is important to note, however, that owing to the potential for severe

adverse events, bedaquiline is not recommended for all patients with MDR
TB.
 Bedaquiline may be used for 24 weeks of treatment in adults with laboratory-
confirmed pulmonary MDR TB when an effective treatment regimen cannot
otherwise be provided.
REFERNENC
ES:
1. Well .B G et al, Definition and Primary infection, Infection disease. In: Dipiro J.
T .Pharmacotherapy handbook. 7th ed., The McGraw-Hill Companies, 2009; p#.531-541.
2. Types of TB, Anti TB therapy, http//www.Types of tuberculosis.htm, Accessed October 5th,
2013.
3. Dipiro J. T et al, Etiology, Reactivation disease, Transmission, Risk factor, Clinical Presentation
of TB, Tuberculosis. In: Plequin C. A.Pharmacotherapy a pathophysiological Approach. 7th ed.,
The McGraw-Hill Companies, 2008; p#.1839-1854.
4. Walker R. and Edverd C. Diagnosis, Infection, Tuberculosis, In: Nehaul L.K. Clinical pharmacy
and therapeutic 3rd ed.,Churchill Livingston London, 2003;p#.585-588.
5. Mehta. D.K. et al, Management, Infection. BNF, 54th ed., British association Royal
pharmaceutical Society of great Britian,2007.p#.110-128.
6. http://www.medscape.com/viewarticle/822098
7. http://www.medscape.com/viewarticle/822098

01/05/2023
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Tuberculosis and its pharmacotherapy

01/05/2023 Infectious diseases (TB) 2

01/05/2023 Infectious diseases (TB) 3

Across the World:

8 million new cases

2-3 million death from the disease

01/05/2023 Infectious diseases (TB)

No. of Cases of TB in 2013=300,000

2013 Pakistan is at 4th position regarding the prevalence of

No. of cases of TB with HIV coinfection is 1500

01/05/2023 Infectious diseases (TB) 5

01/05/2023 Infectious diseases (TB)

01/05/2023 Infectious diseases (TB) 7

Each droplet nuclei contain one to three organisms

During expiratory efforts such as coughing, sneezing.

01/05/2023 Infectious diseases (TB) 8

The incubation period may vary from about two to 12 weeks.

01/05/2023 Infectious diseases (TB) 9

01/05/2023 Infectious diseases (TB) 10

Inhaling air borne particle

Inoculation (puncture wound)

01/05/2023 Infectious diseases (TB) 11

These bacilli are then ingested by pulmonary macrophages.

If these macrophages inhibit or kill the bacilli, infection is aborted.

If the macrophages cannot do this, the organisms continue to multiply.

The macrophages eventually rupture, releasing many bacilli

These mycobacteria are then phagocytized by other macrophages.

Cellular immune reaction occur and may accompanied by spread of bacilli

Granulomas are formed by the action of macrophages and activated T-cell

T-cell clumps together and surround the tubercle bacilli

Bacilli grouped in centered of granuloma

Granulomas become avascular and necrotic because of surrounding fibrosis.

Approximately 90% of patient who experience primary disease have no

01/05/2023 Infectious diseases (TB) 14

01/05/2023 Infectious diseases (TB) 15

eventually will liquefy and spread locally,

leading to the formation of a hole (cavity) in the lungs.

If left untreated, pulmonary TB continue to destroy the lungs,

resulting in hypoxia, respiratory acidosis and eventually death.

01/05/2023 Infectious diseases (TB) 16

01/05/2023 Infectious diseases (TB) 18

Tuberculin skin test: using purified protein derivative (PPD)

01/05/2023 Infectious diseases (TB) 20

Prevent the spread of TB

Find where TB has already spread using contact investigation

Replenish the weakened (consumptive) patient to a state of

01/05/2023 Infectious diseases (TB) 22

STANDARD TB TREATMENT REGIMEN

1st line drugs 2nd line drugs

01/05/2023 Infectious diseases (TB) 23

A. Initial or bactericidal phase

B. Continuation or sterilization phase

01/05/2023 Infectious diseases (TB) 26

01/05/2023 Infectious diseases (TB) 27

Bone/ Joint TB 9 Extend standard therapy to a total of 9 months.

01/05/2023 Infectious diseases (TB) 29

01/05/2023 Infectious diseases (TB) 31

For pulmonary cases, a CXR should be obtained when treatment is

treatment, then obtain sputum.

01/05/2023 Infectious diseases (TB) 35

01/05/2023 Infectious diseases (TB) 36

01/05/2023 Infectious diseases (TB) 37

 Further boosting by the modified-vaccinia-ankara (MVA)85A vaccine failed