PULMONARY TUBERCULOSIS

PULMONARY TUBERCULOSIS
INTRODUCTION
 Pulmonary Usually affects the lungs (80%)

Brain, lymph nodes, the kidneys, bones, and joints

Extrapulmonary (20%)
 Typically spread
Not by contact with items A person needs to inhale
through close/prolonged
or surfaces touched by a only a few of these germs
contact with an infectious
person with TB. to become infected.
individual.

A person cannot get TB Not spread by shaking

from sharing cups, eating someones hand, kissing,
utensils, food or touching bed linens or
cigarettes. toilet seats.
PULMONARY TUBERCULOSIS
EPIDEMIOLOGY
 EPIDEMIOLOGY
Global
In 2010, estimated 8.8 million new
cases of TB globally.
1.1 million deaths among HIV-
negative cases of TB.
0.35 million deaths among people
who were HIV-positive.
Malaysia
In 2010, the incidence was 81.4 per
100,000 population.
While PTB was the commonest form
of TB, extrapulmonary TB (EPTB)
still posed a threat.
NOTIFICATION OF NEW TB CASES IN
MALAYSIA 2005 - 2011
NOTIFICATION OF NEW TB CASES IN
MALAYSIA 2005 - 2011
 PREVALENCE

21-60 years age group Male predominance (65%) 13.9% were foreigners Rate of MDR-TB had
(69.5%) increased from 0.3% in
2005 to 1.3% in 2011
PULMONARY TUBERCULOSIS
TYPES
 TYPES OF TB

I. Active

II. Latent
III. Drug Resistant
IV. Miliary
 ACTIVE TB VS LATENT TB
Active TB Latent TB
Active, multiplying tubercle bacilli in the body Inactive, contained tubercle bacilli in the body

TST or blood test results usually positive TST or blood test results usually positive

Chest x-ray usually abnormal Chest x-ray usually normal

Sputum smears and cultures positive Sputum smears and cultures may be negative

Symptoms like cough, phlegm, chest pain, weakness, weight loss, No symptoms
fever, chills and sweating at night

Often infectious before treatment Not infectious

Can cause death if not treated Can advance to active TB
 DRUG RESISTANT TB

Misuse
Inappropriate use
Poor quality of antibiotics

Multi-drug resistant
TB (MDR-TB) Extensively drug-
resistant TB (XDR-TB)
 MILIARY TB

Rare form of active disease.

Occurs when TB bacteria find their way into the bloodstream.
In this form, the bacteria quickly spread all over the body in tiny nodules and affect multiple
organs at once.

This form of TB can be rapidly fatal.

 HIGH RISK GROUPS

Immuno-compromised patients
Close TB Substance People living in
Diabetes mellitus
contacts HIV infection
abusers and overcrowded
COPD cigarette conditions
End-stage renal disease smokers
Malignancy
Malnutrition
Immuno-suppressant drugs
PULMONARY TUBERCULOSIS
SIGNS & SYMPTOMS
 SIGNS & SYMPTOMS

Cough with thick, cloudy, and

sometimes bloody mucus from
Fever, chills, and night sweats. Fatigue and weakness.
the lungs for more than 2
weeks.

Loss of appetite and Shortness of breath and chest

unexplained weight loss. pain.
PULMONARY TUBERCULOSIS
PATHOPHYSIOLOGY
 PATHOPHYSIOLOGY

Inhalation of Mycobacterium tuberculosis leads to one of four possible

outcomes:
Immediate clearance of the organism
Latent infection
The onset of active disease (primary disease)
Active disease many years later (reactivation disease)
 PATHOPHYSIOLOGY:
PRIMARY INFECTION
Bacilli are carried in droplets (5 to 10 microns) to reach the alveolar spaces.

Bacilli proliferate inside alveolar macrophages and kill the cells.

Infected macrophages produce cytokines and chemokines that attract other phagocytic cells, which form a nodular
granulomatous structure called the tubercle/Gohn focus.

Tubercle enlarges and the bacilli enter local draining lymph nodes.

Tubercle + lymph nodes = Gohn complex.

 PATHOPHYSIOLOGY

PRIMARY INFECTION

LATENT (95%) SECONDARY INFECTION

LOCAL PROGRESSION (5%)
(5%)
 PATHOPHYSIOLOGY:
LOCAL PROGRESSION

Unchecked bacterial growth may lead to haematogenous spread of bacilli to produce disseminated TB.

Cause tuberculosis pneumonia, and infection is disseminated widely to other parts of the body (Ex: liver,
other parts of lungs, brain, other parts of body).

Disseminated disease with lesions resembling millet seeds is termed miliary TB (infection seeds multiple
organs of body with tiny little spots).
 PATHOPHYSIOLOGY:
SECONDARY INFECTION (REACTIVATION TB)

Reactivation TB results from proliferation of a previously dormant bacterium seeded at the time of the primary
infection.

Factors increase risks of secondary infection:

10-Fold Increased Risk: 2-3 Fold Increased Risk:

Host immunity Malnourishment
Human Immunodeficiency Virus Diabetes Mellitus
Transplant Smoking
PATHOPHYSIOLOGY

Source: Khanacademy TB pathogenesis

PULMONARY TUBERCULOSIS
DIAGNOSIS
 LABORATORY INVESTIGATION

a. Microscopy Method
b. Molecular Method
c. Optimal Methods to Detect Drug Resistant TB
d. Rapid Method-Serology Assay
e. Imaging
 MICROSCOPY METHOD

I. Light emitting diode-based fluorescence microscopy (LED FM) &

Fluorescence microscopy.
II. Diagnosis of TB is based on the detection of acid fast bacilli
(AFB) on smears and cultures from clinical specimens.
III. Microscopic examination of sputum using conventional light
microscopy is a common method used in diagnosing PTB.
MOLECULAR METHOD

I. Nucleic Acid Amplification Tests (NAAT)

Rapid results within 24 - 48 hours and has greater PPV (>95%) with AFB smear
positive specimens
Confirm rapidly the presence of Mycobacterium in 50 - 80% AFB smear
negative, culture positive specimens.
II. NAAT can detect the presence of Mycobacterium in specimens
weeks earlier than culture for 80 - 90% patients suspected of
having PTB.
 OPTIMAL METHODS TO DETECT DRUG
RESISTANCE TB

I. Liquid medium & conventional agar medium

II. Line Probe Assay (LPA) Rifampicin resistance & Isoniazid resistance
 SEROLOGY ASSAY

I. Readily available, simple, reliable and cost-effective rapid diagnostic test for TB which can
be applied to a clinically diverse patient population
II. Disadvantages:
Inability to avoid cross reactivity to Bacille Calmette Gurin (BCG) or non-tuberculous mycobacteria (NTM)
and to discriminate active from latent infection.
Not been shown to perform consistently in genetically and immunologically diverse groups.
 IMAGING

I. Chest radiography primary imaging modality for PTB in children, adults and even
pregnant women (with abdominal shield).
II. Computerised tomography (CT) more sensitive in demonstrating endobronchial spread,
lymphadenopathy and pleural complication than chest radiography. It is useful in cases with
high clinical suspicion of TB with normal CXR.
III. Magnetic Resonance Imaging (MRI) considered in special circumstances (children and
pregnant women) as there is no ionising radiation.
 ADDITIONAL PROCEDURE/DIAGNOSTIC
TESTS

For Patient who are unable to spontaneously expectorate adequate sputum specimen & who
are smear negative for AFB.
Sputum induction with nebulised hypertonic saline, fiberoptic bronchoscopy with
bronchoalvelar lavage and gastric lavage techniques.
PULMONARY TUBERCULOSIS
TREATMENT
 GOAL OF THERAPY

1. Eradication of Mycobacterium tuberculosis infection

2. Preventing transmission
3. Preventing relapse of disease
4. Preventing development of drug resistance
TREATMENT OF NEW CASES
 TREATMENT OF NEW CASES

Six-month regimen consisting of two months of daily EHRZ* (2EHRZ) followed by four months of daily
HR* (4HR) is recommended for newly-diagnosed PTB.
Rifampicin should be used for the whole duration of treatment to lower unfavorable outcomes during
maintenance phase.
Rifampicin has a narrow therapeutic index. Hence, its dosage should not be lower than recommended
dosage (10 - 12 mg/kg).
Rifampicin should be increase to higher recommended dose if tolerated. If ethambutol is
contraindicated, streptomycin can be substituted.
DOSING FREQUENCY FOR NEW TB PATIENT
TREATMENT OF PREVIOUSLY TREATED CASE

Optimal duration of treatment for sputum positive PTB is at least six months.
A positive sputum smear may indicate:
The initial phase of therapy was poorly supervised There are co-morbid conditions
Poor quality of anti-TB drugs The patient may have drug-resistant M.
tuberculosis
Doses of anti-TB drugs are below the recommended range
Non-viable bacteria remain visible by microscopy
Resolution is slow because a heavy initial bacillary load
 REGIMEN DURING THE MAINTENANCE
PHASE OF TREATMENT

New patients with pulmonary tuberculosis should receive daily intensive regimen followed by
daily maintenance regimen.

Thrice weekly maintenance regimen can be considered under direct observation.

 FIXED-DOSE COMBINATIONS (FDCs)

Considerable urgency to prevent the emergence of drug-resistant TB.

Rimactazid 300 Sugar Coated Tab
Rimcure 3 FDC Film Coated Tab
Akurit Z Tab
Akurit Tab
Akurit Z Kid Dispersible Tab
Akurit-4
: Isoniazid + Rifampicin
: Isoniazid + Rifampicin + Pyrazinamide
: Isoniazid + Rifampin (Rifampicin) + Pyrazinamide
: Isoniazid + Rifampin (Rifampicin)
: Isoniazid + Rifampin (Rifampicin) + Pyrazinamide
: Isoniazid + Rifampin (Rifampicin) + Pyrazinamide + Ethambutol
 DIRECTLY OBSERVED THERAPY (DOT)

Should be adopted to improve compliance in tuberculosis (TB) management.

Patient-centred, incorporating negotiations, and patients characteristics and preferences.
Prompt reminders should be sent to TB patients.
Contact tracing should be done intensively, including home visits to retrieve contacts who do not come
for screening.
Train non-governmental organisation staff, community members and peers.
PULMONARY TUBERCULOSIS
ADVERSE DRUG REACTIONS
 CLASSIFICATION OF ADR OF ANTI-TB DRUGS

ADR = Harm associated with the use of given medication at a normal dosage during normal use
Occur within early stage of the treatment compared to the later stage
Nausea
Troublesome but not Tiredness Treat symptomatically without
serious Pruritus interrupt treatment
Minor rashes

Need immediate Severe skin reactions

Eg: Steven-Johnson Syndrome, Toxic Epidermal Necrosis,
discontinuation of the Drug Rash with Eosinophilia and Systemic Symptoms
treatment Hepatitis
SYSTEMS AFFECTED BY ANTI-TB DRUGS

4.8%
7.1%
Hepatobiliary
9.5%
GI tract
Skeletal system
14.3% 57.1% Skin
Renal

Source: Clinical Practice Guidelines Management of Tuberculosis in Malaysia (2012)

 RISK FACTORS OF ADR OF ANTI-TB DRUGS

Age > 40 yrs Extra-pulmonary TB

Overweight / obesity Multi-drug-resistant TB medication
Smoking CD4 count < 350 cells/mm3
Alcoholism Hepatitis B or C virus infection
Anaemia Concomitant use of other hepatotoxic
Baseline ALT or AST > 2x upper limit drug
of normal
HIV infection Source: Clinical Practice Guidelines Management of Tuberculosis in Malaysia (2012)
 COMMON ADR OF AKURIT-4

Abnormal Nausea &

Anorexia Fever
LFTs vomiting

Headache Dizziness Malaise Weakness

Rash Itching
Source: Akurit 4 Tablet - Uses, Side-effects, Reviews, and Precautions - Lupin - Tablet Wise - India. (n.d.). Retrieved from http://www.tabletwise.com/akurit-4-tablet
 ADR OF INDIVIDUAL DRUGS
ADRs Isoniazid Rifampicin Pyrazinamide Ethambutol
Hepatotoxicity
Liver
Jaundice
Optic Neuritis
Eyes Decreased acuity, color
blindness or visual defects
PNS Peripheral Neuritis
Pruritus
Skin Urticaria
Photosensitivity
Respi Symp SOB
Muscle Abdominal pain
Source: BNF 69
 ADRs Isoniazid Rifampicin Pyrazinamide Ethambutol
Epigastric distress
GI Symp Diarrhea
Constipation
Anemia
Blood haemolytic & aplastic haemolytic sideroblastic
Thrombocytopenia
Renal failure

Renal Urine, saliva and other body

secretions coloured orange-
red
Gout
Other Arthralgia
Hyperreflexia
Source: BNF 69
 WHICH AGENT IS MOST LIKELY TO CAUSE A
GIVEN SYMPTOM OR ADVERSE EFFECT?

Most likely cause Least likely cause

Hepatitis ALT/AST predominant Isoniazid Pyrazinamide Rifampicin Ethambutol (very
rare)
Hepatitis Cholestatic Rifampicin
Upeer GIT symptoms Rifampicin Pyrazinamide Isoniazid Ethambutol
Arthralgia Pyrazinamide Rifampicin Isoniazid Ethambutol
(flu like syndrome) (drug induced lupus)
Hypersensitivity (fever + rash + other) Isoniazid Rifampicin Pyrazinamide Ethambutol
Among antiTB drugs, pyrazinamide is the commonest drug associated with ADR
Source: Clinical Practice Guidelines Management of Tuberculosis in Malaysia (2012)
 COMMENTS ON INDIVIDUAL DRUGS

Isoniazid: Rifampicin:
Risk of hepatotoxicity increases with: Flu like syndrome more likely with intermittent therapy:
Age Myalgia Malaise
Arthralgia Mild haemolysis
Heavy alcohol consumption Fever
Liver disease Interrupted therapy may be associated with:
Rarely neuropathy may effect optic nerve Shock Haemolytic anaemia
Acute renal failure Thrombocytopenic purpure
These features are an absolute contraindication to re-
challenge
 COMMENTS ON INDIVIDUAL DRUGS

Pyrazinamide: Ethambutol:
Elderly are more prone to GI side effects and Visual disturbance risk is increased with longer
hepatitis. duration and higher dose.

Avoid pyrazinamide if pre-existing history of Occurs after months of therapy.

clinical gout. Visual acuity, colour vision and fields should be
checked monthly.
Risk of ocular toxicity is increased in renal
impairment.
 CONTRAINDICATION OF AKURIT-4

Avoid Akurit-4 Tablet with tyramine-rich food such as cheese, smoked fish, meats and
some types of beer
Hypersensitivity
Alcohol
Severe liver / renal disease
Children aged below 3 yrs
Pregnancy Source: V. Gupta, (2017), Medicine Overview of Akurit-4 Tablet.
Retrieved from https://www.1mg.com/drugs/akurit-4-tablet-147003
CONTRAINDICATION OF INDIVIDUAL DRUGS

Isoniazid Rifampicin Pyrazinamide Ethambutol

Drug-induced Jaundice Gout Optic neuritis

liver disease Acute porphyria Severe hepatic Poor vision
Renal Concomitant damage
impairment administration of
drugs
metabolized by
hepatic enzymes

Source: BNF 69
PULMONARY TUBERCULOSIS
PHARMACEUTICAL CARE ISSUES
(MONITORING PARAMETER)
 MONITORING PARAMETER

1. Therapeutic Outcome

2. Drug Therapy Monitoring

THERAPEUTIC OUTCOME
 DRUG MONITORING THERAPY
Drug Adverse effects Monitoring
Cutaneous reactions
GI reactions (nausea, anorexia, abdominal pain)
Flu-like syndrome Liver enzymes
Rifampicin Hepatotoxicity Interacting drugs as needed (e.g., warfarin)
Severe immunologic reactions
Orange discoloration of bodily fluids (sputum, urine, sweat, tears)
Drug interactions due to induction of hepatic microsomal enzymes.
Asymptomatic elevation of aminotransferases
Clinical hepatitis
Fatal hepatitis LFT monthly in patients who have preexisting liver
Peripheral neurotoxicity disease or who develop abnormal liver function that
Isoniazid CNS effects does not require discontinuation of drug
Lupus-like syndrom Dosage adjustments may be necessary in patients
Hypersensitivity receiving anticonvulsants or warfarin
Monoamine poisoning
Diarrhea
 Drugs Adverse effects Monitoring
Hepatotoxicity
GI symptoms (nausea, vomiting)
Nongouty polyarthralgia
Serum uric acid can serve as a surrogate marker for adherence
Pyrazinamide Asymptomatic hyperuricemia
LFTs in patients with underlying liver disease
Acute gouty arthritis
Transient morbilliform rash
Dermatitis

Baseline visual acuity testing and testing of color discrimination

Retrobulbar neuritis
Monthly testing of visual acuity and color discrimination in patients
Ethambutol Peripheral neuritis,
taking >1520 mg/kg having renal insufficiency or receiving the drug
Cutaneous reactions
for >2 months
PULMONARY TUBERCULOSIS
PHARMACEUTICAL CARE ISSUES
(DRUGS & DOSE SUGGESTION)
 PHARMACEUTICAL CARE ISSUES
(DRUGS & DOSE SUGGESTION)

When to stop Anti-TB Drugs?

Serum transaminase level reaches

Serum transaminase level reaches
3 X ULN for patients with symptoms
5 X ULN for those without symptoms
suggestive of hepatitis

Source: Clinical Practice Guidelines Management of Tuberculosis in Malaysia (2012)

RIF = Rifampicin
INH = Isoniazid
PZA = Pyrazinamide
PHARMACEUTICAL CARE ISSUES
(DRUGS & DOSE SUGGESTION)
PULMONARY TUBERCULOSIS
REFERENCES
 REFERENCES

Khanacademy; (2017); TB pathogenesis. Retrieved from https://www.khanacademy.org/science/health-and-

medicine/infectious-diseases/tuberculosis/v/tb-pathogenesis
WebMD; (2017); Tuberculosis (TB) Symptoms. Retrieved from http://www.webmd.com/lung/tc/tuberculosis-tb-symptoms
MedlinePlus; (2017); Pulmonary tuberculosis. Retrieved From https://medlineplus.gov/ency/article/000077.htm
Medscape; (2017); Tuberculosis: Practice Essentials, Background, Pathophysiology. Retrieved from
http://emedicine.medscape.com/article/230802-overview#a1
SSMJ Vol 6. No 1; (2013); Robert L. Serafino Wani MBBS, MRCP, MSc; Tuberculosis 2: Pathophysiology and microbiology of
pulmonary tuberculosis. Retrieved from http://www.southsudanmedicaljournal.com/archive/february-2013/tuberculosis-2-
pathophysiology-and-microbiology-of-pulmonary-tuberculosis.html
 REFERENCES

Akurit 4 Tablet Uses, Side-effects, Reviews, and Precautions - Lupin - Tablet Wise - India. (n.d.). Retrieved from
http://www.tabletwise.com/akurit-4-tablet
V. Gupta. (2017). Medicine Overview of Akurit-4 Tablet. Retrieved from https://www.1mg.com/drugs/akurit-4-tablet-147003
T. E. Herchline. (2016). Tuberculosis. Retrieved from http://emedicine.medscape.com/article/230802-overview
Joint Formulary Committee. (2015). British National Formulary 69. London: BMJ Publishing and the Royal Pharmaceutical
Society.
Ministry of Health. (2012). Clinical Practice Guidelines Management of Tuberculosis (3rd Edition). Malaysia Health Technology
Assessment Section, Medical Developmeent Division.
 REFERENCES

Flick, L., Tuberculosis, M., Tuberculosis, P., & Program, C. (1998). Guidelines for the Management of Adverse Drug Effects of
Antimycobacterial Agents, (November).
Khan, R. A. (n.d.). Pharmacotherapy of Tuberculosis Management.
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Ministry Of Health Malaysia. (2016). Ministry of Health Medicines Formulary, (MARCH).
Saukkonen, J. J., Cohn, D. L., Jasmer, R. M., Schenker, S., Jereb, J. A., Nolan, C. M., Hepatotoxicity, A. T. S. (2006). Hepatotoxicity
of Antituberculosis Therapy, Retrieved from 174, 935952. https://doi.org/10.1164/rccm.200510-1666ST
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