Tuberclosis pharmacotherapy

TUBERCULOSIS
DR.MUHAMMAD USAMA KHAN
HAMDARD UNIVERSITY
ISALAMABAD
PAKISTAN

Introduction
 TB remains one of the most common causes of
death amongst infectious diseases worldwide.
 Despite the fact that Mycobacterium tuberculosis
colonizes few hosts other than man and survives
only briefly when isolated in the environment,
efforts to eliminate the disease have failed to date.
 TB has staged a comeback in the US and other
parts of the world because of shifts in the
population considered endemic for TB, healthcare
policies changes, ↑ in the number of
immunocompromised individuals, and
development of drug resistance.

TB Burden 2012
 8.6 million people fell ill with TB in 2012,
including 1.1 million cases among people
living with HIV
 In 2012, 1.3million people died from TB,
including 320000 among people who were
HIV-positive

Epidemiology of TB Pakistan…
 Tuberculosis (TB) is a massive public health problem and
according to World Health Organization, (WHO) Pakistan ranks
5th in the countries having high disease burden.
 It contributes 26% of avoidable deaths among adults and
children in our country.
 The present annual incidence of open TB cases is estimated to
be between 231/100,000 persons and subsequently about
361,000 new cases of TB are added every year in Pakistan
http://data.worldbank.org/indicator/SH.TBS.INCD

Epidemiology of TB…
 Four out of 5 TB patients in Pakistan still remain
undetected, untreated and inadequately managed.
 One untreated or poorly treated “open case” of TB can
make 10-15 people more patients in a year’s time.
 Lack of proper diagnostic equipment and skills, irrational
prescription and non-availability of essential anti TB drugs
are among the major contributing factors of various
complications including emerging resistance.
 Multi Drug Resistant TB is a contributing factor to
increasing costs, mortality and duration of treatment.
 A simple TB case management incurs a cost of 6000
rupees for the treatment of 9 months while a MDR TB
case, which requires treatment for 2 years, costs about
300,000 rupees

Etiology of TB
 TB is caused by M. tuberculosis, an
aerobic, non-spore-forming bacillus.
 Also called Acid-fast bacillus (AFB).
 M. tuberculosis replicates slowly (q 24hrs)
(20-40 minutes with other organisms).
 M. tuberculosis thrive well in environment
where O2 tension is high such as renal
parenchyma, growing ends of bones.

Mycobacterium species include:
M. tuberculosis complex: M. tuberculosis, M. bovis,
M. africanum
Mycobacteria other than tuberculosis: Around 15 are
recognised as pathogenic to humans and some cause
pulmonary disease resembling TB. They have been
found
in soil, milk and water. They are also referred to as
atypical mycobacteria.
Mycobacterium leprae: The cause of leprosy.

Pulmonary (respiratory) TB
extrapulmonary (non-respiratory) TB.
Sites of extrapulmonary disease include the pleura, lymph
nodes, pericardium, kidneys,meninges, bones and joints,
larynx, skin, intestines, peritoneum and eyes.
Pulmonary TB may arise from exogenous reinfection or
endogenous reactivation of a latent focus remaining from
the initial infection.

Transmission
 Tubercle bacilli are transmitted through the air by
aerosolized droplet nuclei that are produced when a
person with pulmonary or laryngeal TB coughs, sneezes,
speaks, or sings.
 Droplet nuclei may also be produced by other methods
such as bronchoscopy, endotracheal intubation,
processing of secretions in labs and hospitals.
 The nuclei, which contains one to 3 M. tuberculosis
organisms, are small enough to remain airborne for long
periods of time and to reach the alveoli within the lungs
when inhaled.

Transmission…
 Tubercle bacilli are not transmitted on inanimate
objects such as dishes, clothing, or beddings, and
organisms deposited on skin or intact mucosa do
not invade tissues.
 Several factors influence the likelihood of
transmission of M. tuberculosis, including
 the number of organisms expelled into the air,
 the length of time an exposed person breathes the
contaminated air,
 and presumably the immune status of the exposed
individual.

Transmission…
 Family household contacts, especially children, and
people working or living in an enclosed environment
(hospitals, prisons, nursing homes) with an infected
person are at increased risk.
 Individuals with impaired cell-mediated immunity are
thought to be more likely to become infected with M.
tuberculosis after exposure than persons with normal
immune functions.
 Most effective means of reducing transmission is by
treating infected patients with effective chemotherapy.

Pathophysiology of TB
 Latent Infection vs. Active Disease (TB).
 Upon inhalation, droplet nuclei settle into the
bronchioles and alveoli of the lungs.
 Development of infection in the lungs will
depend on virulence and other factors.
 Individuals with latent TB infections are not
infectious and cannot transmit the
organisms.

Pathophysiology of TB…
 The extent of the disease produced by M. tuberculosis in
humans depends on the size of the inoculum of bacteria
inhaled (most common route of acquisition) and the
immune status of the host at the time of initial infection and
at a later time.
 If the patient is immunocompromised at the time of initial
infection, the disease will more likely progress into
bacterial pneumonia at the site of implantation, known as
primary progressive disease.
 In the remaining group whose immune system is
competent, the infection will usually be halted after a brief
period of bacillary dissemination.

 In individuals who inhale a massive inoculum of
organisms, however, clinical disease may occur
despite an intact immune system.
 In immunocompetent individuals, the 1º infection is
held in check due to the development of T cell-
mediated hypersensitivity that usually occurs 4-8
weeks after initial infection.
 At this time, the patient will demonstrate a positive
reaction to a TST, and any remaining viable
organisms within the body will be walled off in
caseating granulomas.

 1/10 persons with symptomatic 1º infection will at
some later date develop active TB (reactivation
disease) because the immune system fails to
contain the organism.
 This most often presents as pulmonary
tuberculosis (PTB), although extrapulmonary
tuberculosis (CNS, renal, hepatic, GI, skeletal) is
not uncommon.

Diagnosis of Tuberculosis
 The most common form of TB in adults is
post-primary pulmonary tuberculosis
(PTB).
 Has great epidemiological significance.
 Based on clinical, radiological and/or
bacteriological evidence.

Signs & Symptoms of PTB
 Persistent cough (more than 2 weeks).
 Cough with blood-stained sputum
(hemoptysis).
 Dyspnea, chest pain, hoarseness of voice.
 Fever with night sweats.
 Loss of weight and loss of appetite.

Signs & Symptoms of PTB…
 Consolidation.
 Pulmonary fibrosis.
 Stony dullness caused by pleural effusion.

Laboratory Investigations
 Sputum direct smear for AFB (3 specimens).
 C&S using egg-based media.
 Chest X-ray often reveals lesions in the
apical and posterior segments of the upper
lobes (soft, usually little or no fibrosis).
 Mantoux Test (Tuberculin PPD Skin Test)
has some role in diagnosis.

Laboratory Investigations
 Erythrocyte Sedimentation Rate (ESR) has
little role and cannot be recommended for
routine use in the diagnosis and follow-up
evaluation of patients.
 Techniques utilizing PCR can give rapid
results, but are expensive.

Diagnosis of Extra-pulmonary TB
 Due to lympho-hematogenous dissemination
during 1º TB infection.
 Symptoms are often non-specific: anorexia,
fever, weight loss.
 Specific features related to the organ
involved.
 TB lymphadenitis, GU TB, TB of joints and
bones, miliary TB.

High Risk Group
 Contacts of sputum positive TB cases.
 Persons with HIV infections.
 Immigrants from countries with high
prevalence.
 Persons in institutions such as prison or drug
rehabilitation centers.
 Persons with other risk factors (DM, silicosis,
prolonged corticosteroids and
immunosuppressive therapies).

Treatment of Active TB
A. GOALS OF TREATMENT
 Cure the individual to prevent morbidity and
mortality.
 Prevent relapse of the disease.
 Minimize transmission of M. tuberculosis.
 Prevent emergence of MDR-TB.

B. Essential First Line Drugs
i. Isoniazid, INH (H)
ii. Rifampicin (R)
iii. Pyrazinamide (Z)
iv. Streptomycin (S)
v. Ethambutol (E)

C. DOTS Regimen
 Directly observed treatment (DOT) is an
important element in the internationally
recommended policy package for TB control.
 DOTS remains at the heart of the Stop TB
Strategy.

C. DOTS Regimen
 Directly observed treatment means that an
observer watches the patient swallowing their
tablets, in a way that is sensitive and supportive
to the patient's needs.
 This ensures that a TB patient takes the right
antituberculosis drugs, in the right doses, at the
right intervals.

C. DOTS Regimen
The five elements of DOTS:
 Political commitment with increased and sustained
financing.
 Case detection through quality-assured bacteriology.
 Standardized treatment, with supervision and patient
support.
 An effective drug supply and management system.
 Monitoring and evaluation system, and impact
measurement.

D. Treatment Regimens
 Effective treatment of TB requires substantial
period (minimum 6 months) of intensive drug
therapy with at least two (2) bactericidal drugs
that are active against the organism.
 The initial phase of treatment is crucial for
preventing the emergence of resistance and for
ultimate outcomes of therapy.

D. Treatment Regimens
 The course of treatment is divided into: Initial
(Intensive) Phase and the Continuation (Maintenance)
Phase.
 The 2-month Intensive Phase with 3 or 4 drugs is to
rapidly convert the sputum and improve clinical
symptoms.
 The 4-month Continuation Phase with 2 or 3 drugs
has a sterilizing effect to eliminate the remaining bacilli
and prevent relapse.

Category II: Treatment Failure,
Relapse, Treatment after Default
 DO NOT initiate conventional therapy as above.
 Send sputum sample for C &S.
 Refer case to Respiratory or Chest Physician.
 Treatment should be based on C&S results and
clinical response.

Category III: Chronic Case
 DO NOT initiate conventional therapy as above.
 Send sputum sample for C &S.
 Refer case to Respiratory or Chest Physician.
 Treatment should be based on C&S results and
clinical response.

Drug and Multidrug-Resistant TB (MDR-TB)
 Anti-tuberculosis (TB) drug resistance is a major
public health problem that threatens the success
of DOTS.
 MDR-TB is a specific form of drug-resistant TB
due to a bacillus resistant to at least isoniazid and
rifampicin, the two most powerful anti-TB drugs.
 “MDR-TB” is not synonymous to “Chronic TB”.
 MDR-TB patients respond poorly to shortcourse
chemotherapy and need to be treated intensively
and for up to 24 months with a regimen based on
reserve antituberculosis drugs…

Therapeutic Options IN HIV/AIDS
Isoniazid, rifampin, pyrazinamide, and
ethambutol for 2 months (daily or 5x/week),
followed by isoniazid and rifampin for 4
months (daily, 5x/week, or 3x/week).
Alternatively, isoniazid, rifampin, and
ethambutol for 2 months (daily or 5x/week),
followed by isoniazid and rifampin for 7
months (daily or 5x/week)

Case
 M.W., a 36-year-old woman, is admitted to the hospital with a 2-month
history of cough, which has recently become productive. She is also
experiencing fatigue, night sweats, and has lost 15 pounds. Other
medical problems include diabetes mellitus, which is controlled with 10
units of NPH insulin daily, and poor nutritional status secondary to
frequent dieting. M.W. works as a volunteer in a nursing home several
days a week. Recently, it was discovered that two patients who she had
been caring for had undiagnosed active tuberculosis.
 M.W.'s physical examination was normal, but her chest radiograph
revealed bibasilar infiltrates. A tuberculin purified protein derivative
(PPD) skin test, sputum collections for cultures and susceptibility
testing, and a sputum AFB smear were ordered as part of M.W.'s
diagnostic workup. Initial laboratory test findings were within normal
limits.
 The result of her tuberculin PPD skin test, read at 48 hours, was a
palpable induration of 14 mm. Her sputum smear was positive for AFB,
and additional sputum cultures for M. tuberculosis were ordered to
confirm the diagnosis of active TB disease.

Q. 1. What subjective and objective findings does M.W. have
that are consistent with active TB disease?
 Subjective Findings:
 M.W.'s history of cough (which gradually became productive),
bibasilar infiltrates, fatigue, and night sweats are consistent with
the classic symptoms of active TB.
 The cough may be nonproductive early in the course of the
illness, but with subsequent inflammation and tissue necrosis,
sputum is usually produced and is key to most of the diagnostic
studies.
 Anorexia from TB, along with frequent dieting, may have resulted
in M.W.'s weight loss. Other symptoms of TB can include fever,
pleuritic pain secondary to inflammation of lung parenchyma
adjacent to the pleural space, and general malaise. Dyspnea is
unusual unless there is extensive disease.

 Objective Findings:
 M.W. has a chest radiograph consistent with a lower respiratory
tract infection. In pulmonary TB, nodular infiltrates are usually
found in the apical or posterior segments of the upper lobes, but
markings may be found in any segment.
 M.W. also has a positive sputum smear for AFB, a positive PPD
skin test (14 mm), and diabetes mellitus, which is a risk factor for
TB. Although her laboratory test results are within normal limits,
peripheral blood leukocytosis and anemia are the most common
hematologic manifestations of TB.18 The white blood cell count
is normal or slightly increased, and an increase in monocytes
and eosinophils may be observed.

Q.2. What is tuberculin skin testing? How should
the results be interpreted in M.W.?
 Ans. 2.
 The tuberculin skin test (Mantoux method) has been used as a
diagnostic tool for infection with M. tuberculosis for decades, but a
positive skin test is not necessary for the diagnosis of active TB
disease.
 The test is frequently referred to as the PPD test, which contains a
protein prepared from a culture of the tubercle bacilli. The skin test is
performed by injecting 0.1 mL of solution containing 5-TU PPD
intracutaneously into the volar or dorsal surface of the forearm.
 An induration ≥5 mm in diameter read 48 to 72 hours after injection is
considered to be a positive reaction in an individual with a recent history
of close contact with a person with active TB.
 An induration ≥10 mm in diameter is considered to be a positive
reaction in persons with clinical conditions that put them at increased
risk for TB, such as diabetes mellitus, silicosis, chronic renal failure,
malnutrition, leukemia, lymphoma, gastrectomy, jejunoileal bypass, and
weight loss of >10% of ideal body weight.

Q. 3 Because M.W.'s Mantoux PPD skin test is positive, does
this confirm her diagnosis of active TB?
Ans. 3
 No. M.W.'s positive reaction to 5-TU PPD alone does not
confirm active TB disease.
 It merely signifies that she has previously been infected
with M. tuberculosis. To confirm the diagnosis of active
TB disease in M.W. and other patients, M. tuberculosis
must be isolated from sputum, gastric aspirate, spinal
fluid, urine, or tissue biopsy, depending on the site of
infection

Q.4. How should treatment be initiated in M.W pending the
results of the sputum culture and sensitivity?
Ans. 4
 INH 5mg/kg max 300mg
 Rifampacin 600 mg
 Ethambutal 15-25 mg/kg/day
 Pyrazinamide 15-50 mg /kg/day

Q.5. What are the monitoring parameters for M.W therapy?
Ans.5
 ESR
 Blood CP
 LFT’s
 Fundoscopic examination
 Extremities
 Urine

Q.6 What are the possible side effects of ATT treatment
 INH: GI Intolerance: -Nausea, abdominal pain common-Vomiting less common, Peripheral
neuropathy: -dose-related -<0.2% will have, rash, Hepatitis
 -10-20% of persons who take isoniazid will develop asymptomatic LFT increase
 -In most cases these will resolve with continued treatment
 Rifampacin: GI side effects
 • Orange urine/body fluids (sweat) -harmless but may stain contact lenses,
 clothing-need to let patients know beforehand Hepatitis:
 -occurs in about 0.6% of patients, flu like syndrome
 Pyrazinamide—Side Effects
 • GI symptoms
 • Arthralgias (joint pain)
 •Rash
 • Hyperuricemia (elevated uric acid) uric acid)
 -usually asymptomatic
 -may precipitate gout, kidney stones
 -TB medications do not usually require discontinuation
 Hepatitis dose related

 Ethambutol— Side Effects
 • Optic neuritis:-blurred vision
 -”spots” in patient’s field of vision-red/green
color blindness• Dose related Dose related
 • Uncommon with intermittent tx
 • Drug should be discontinued
 • Usually reversible if stopped right away

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