TB lecture Note in Power point

1. Tuberculosis (TB)
AYANA TADESSE (B.Pharm, M.Sc)
Wollega University, Department of Pharmacy

2. Introduction
• TB is an infectious disease caused by a bacteria; that most
commonly affects the lungs.
• Is a chronic infectious disease caused by bacteria called
Mycobacterium tuberculosis
– Occasionally by M.bovis and M.africanum
• Tubercle bacilli can remain dormant in tissues and persists for
many years
• 80% of MTB affects the lungs….PTB while 20% organs other
than the lung parenchyma…EPTB
• TB infection occurs when a person carries the tubercle bacilli
inside the body, but the bacteria are in small number and are
dormant

3. Epidemiology of TB
• M. tuberculosis affects 1/3 of world population
• Global report 2013, 8.6 million incident cases of TB globally of
which 1.1 million were among people living with HIV
• Ethiopia is one of the 22 high burden countries (HBCs) and TB
remains one of the leading causes of mortality due to
communicable diseases in the country.
– According to the 2014 WHO report, the prevalence and
incidence of all forms of TB are 211 and 224 /100,000
population, respectively
– Among estimated all new TB cases, 13% are HIV co-
infected
3

4. Con’t
• Ethiopia is also one of the high TB/HIV and multi-drug
resistant TB (MDR TB) burden countries.
– According to the recent national TB drug resistance
surveillance report, 2.3% of new TB cases and 17.8% of
previously treated TB cases were estimated to have MDR
• About 10% of infected persons with normal immunity will
develop TB at some point in life if not treated.
– 5% during first 1–2 yrs post infection, another 5% later in
life
• Persons with weak immunity at increased risk of progressing
to TB disease
– Untreated HIV infection highest risk factor: risk of
developing TB disease is 7%–10% each year;
– Children <5 years of age also at increased risk

5. Transmission of M. tuberculosis
 M. tb spread via airborne
particles called droplet
nuclei
 Expelled when person with
infectious TB coughs,
sneezes, shouts, or sings
 Transmission occurs when droplet nuclei inhaled and reach
the alveoli of the lungs, via nasal passages, respiratory tract,
and bronchi

6. Probability TB Will Be Transmitted
 Susceptibility of the exposed person
 Infectiousness of person with TB (i.e., number of bacilli TB
patient expels into the air)
 Environmental factors that affect the concentration of M. tb
organisms
 Proximity, frequency, and duration of exposure (e.g., close
contacts)
 Can be transmitted from children, though less likely

7. Pathogenesis
Droplet nuclei containing tubercle
bacilli are inhaled, enter the lungs, and
travel to the alveoli.
Tubercle bacilli multiply in the alveoli.

8. Con’t
A small number of tubercle bacilli
enter the bloodstream and spread
throughout the body. The tubercle
bacilli may reach any part of the
body, including areas where TB
disease is more likely to develop
(such as the brain, larynx, lymph
node, lung, spine, bone, or
kidney).

9. Con’t
Within 2 to 8 weeks, special immune cells
called macrophages ingest and surround
the tubercle bacilli. The cells form a
barrier shell, called a granuloma, that
keeps the bacilli contained and under
control (LTBI).
If the immune system cannot keep the
tubercle bacilli under control, the bacilli
begin to multiply rapidly (TB disease). This
process can occur in different areas in the
body, such as the lungs, kidneys, brain, or
bone.

10. 10
 Latent TB Infection (LTBI)
•Occurs when person breathes in bacteria
and it reaches the air sacs (alveoli) of lung
• Immune system keeps bacilli contained
and under control
• Person is not infectious and has no
symptoms
Con’t

11. 11
Con’t
 TB disease
•Occurs when immune system cannot
keep bacilli contained
• Bacilli begin to multiply rapidly
• Person develops TB symptoms

12. 12
Sites of TB Disease
• Pulmonary TB occurs in the lungs
– 80% of all TB cases are pulmonary
• Extrapulmonary TB occurs in places other than the lungs,
including the:
– Larynx
– Lymph nodes
– Brain and spine
– Kidneys
– Bones and joints
• Miliary TB occurs when tubercle bacilli enter the
bloodstream and are carried to all parts of the body

13. 13
Persons at Risk for Developing TB Disease
• Persons at high risk for developing TB disease
fall into 2 categories
– Those who have been recently infected
– Those with clinical conditions that increase their
risk of progressing from LTBI to TB disease

14. 14
Increased Risk for Progression to TB Disease
 Persons more likely to progress from LTBI to TB disease
include
– HIV infected persons
– Those with history of prior, untreated TB
– Underweight or malnourished persons
– Injection drug use
– Those receiving TNF-α antagonists for treatment of
rheumatoid arthritis or Crohn’s disease
– Certain medical conditions

15. Clinical Presentation
• Variable and depends on the specific organ affected
by the disease.
• The general symptoms of TB (pulmonary or extra-
pulmonary):
– Weight loss
– fatigue, malaise
– low grade fever
– night sweats
– loss of appetite
– malnourished and chronically ill children with failure to
thrive

16. Con’t
• Additional Sx & symps of pulm TB:
– Cough that lasts for more than 2 weeks with or without
sputum production
– Chest pain
– Haemoptysis
– Difficulty breathing
• Sx & Symps of possible extrapulmonary TB:
– Blood in the urine (TB of the kidney)
– Headache/confusion (TB meningitis)
– Back pain (TB of the spine)
– Hoarseness (TB of the larynx)
– Loss of appetite, unexplained weight loss
– Night sweats, fever, Fatigue

17. Con’t
• Pts with HIV may have atypical presentation.
• TB in the elderly is easily confused with other
respiratory diseases.
N.B. Suspect TB in any person who presents
with a Hx of cough of at least two weeks
duration.

18. Diagnosis
 Medical history
 Physical examination
– Dullness to chest percussion, rales, and increased
vocal fremitus are observed frequently on
auscultation.
– Cannot be used to confirm or rule out TB disease
 Test for TB infection
– TST (tuberculin skin test): the most widely used
screening method which uses PPD.

19. Con’t
 Chest radiograph (X-ray)
• Chest abnormalities suggest, but do not confirm,
TB disease
• Posterior-anterior view is standard
• Apical/posterior areas of upper lobe or superior
areas of lower lobe often show abnormalities
• In immuno-suppressed (e.g., HIV infected),
lesions may have atypical appearance.
• Active versus inactive disease cannot be
determined from chest radiograph alone

20. Chest Radiograph with Lower Lobe Cavity

21. Con’t
 Bacteriologic examination
• Specimen collection
– Collect at least 3 sputum specimens at 24-hr intervals,
at least 1 in the morning
• AFB smear classification
• Culture and identification
– Remains gold standard for confirming diagnosis of TB
and phenotypic identification of medicine resistance.
• Drug-susceptibility testing

22. Treatment
 TB Case definitions
• Tuberculosis suspect.
– Any person who presents with symptoms or signs
suggestive of TB.
• Case of TB
– A definite case of TB (defined below) or one in which a
health worker (clinician or other medical practitioner) has
diagnosed TB and has decided to treat the patient with a
full course of TB treatment.
• Definite case of TB
– A pt with M. tb complex identified from a clinical
specimen, either by culture or by a newer method such as
molecular line probe assay.
– Sputum +Ve for AFB + Sx & Symps of TB

23. Con’t
 Goals of Therapy
– Cure the TB patient and restore quality of life and
productivity
– Prevent death from active TB or its late effects
– Prevent TB relapse
– Prevent the development and transmission of
medicine resistance
– Decrease transmission.
– Ensure adherence and completion of therapy

24. Con’t
 Non-pharmacologic
– Counselling
– Good nutrition
– Adequate rest
– Admission for severely ill patients

25. Con’t
 Pharmacologic
• Drug therapy is the corner stone of TB mngmt
• Rx is with a c/bn of 4 or more anti-TB medicines.
• The Rx is standardized by:
– putting pts into d/t Rx grps based on smear status and
previous Hx of Rx for TB
• TB treatment strategy is referred to as DOT.
– Health-care worker watches pt swallow each dose
– It is preferred management strategy for all pts
– Can reduce acquired drug resistance, Rx failure, and
relapse

26. Treatment of Latent TB Infection (LTBI)
 Can be achieved by admn of prophylactic INH or Rifampicin.
 IPT
• Prophylactic administration of INH for prevention of
development of active TB
• Benefit of IPT
– Reduce the risk of TB by 33- 67% for up to 5 years, efficacy
greater for people who are TST positive
– Prevent active TB from latent TB infection, i.e. reactivation
as well as primary TB
• Dose: INH 300mg/day for 6 months for adults and 10mg/kg
for children
– Provide pyridoxine supplementation
• Altern: Rifampicin daily dose for 4 mths.

27. Treatment of TB Disease
 Rationale for Multiple Drug Therapy
• To prevent resistance by additive effect
• 3 Distinct Populations of M. tb
– Actively dividing extracellular bacilli (in cavities 107-109
organisms)Isoniazid (INH), Rifampin (RIF), streptomycin
(SM)
– Bacilli within the lesion (105-107)Pyrazinamide (PZA), RIF,
INH
– Bacilli within the macrophage (104-106) INH, Rifampin,
quinolones
• Combination therapy Very Short Course (6 mo)
– rapid elimination of extracellular organisms (decrease
infectivity)
– elimination of slowly dividing organisms within lesions and
macrophages

28. Con’t
 Phases of therapy
• Induction Phase: ~ 2 months
– Destroy extracellular organisms
– Daily Dosing
– INH, Rifampin, PZA, Ethambutol
• Continuation Phase: Generally INH + Rif for 4 months
after (-)sputum
– HIV positive generally require longer therapy, ? Rifampin
(69 months)
– Longer regimens may be necessary if cavitary lesions
present, miliary, meningeal, bone/joint TB (12 months)

29. Con’t
 TB Drugs
• The 1st line anti-TB medicines:
– Rifampicin(R)
– Ethambutol (E)
– Isoniazid (H)
– Pyrazinamide (Z) and Streptomycin (S)
• The FDCs available for adults and adolescents:
– RHZE 150/75/400/275mg
– RHZ 150/75/400mg
– RH 150/75mg
– EH 400/150mg

30. 1st-line agents
•INH
•RIF
•PZA
•EMB
Injectable agents
•SM
•KM
•AMK
•CM
Fluoroquinolones
•Oflox
•Levo
•Moxi
•Gati
2nd-line Oral agents
"3rd-line" agents
•ETA/PTA
•PASA
•CYS
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
Classification of drugs into 5 groups based on
hierarchy of efficacy and safety including 2nd-line
drugs

31. Con’t
• Four drug therapy preferred for active TB (for the
first 2 months only)
– INH 5mg/kg (maximum 300 mg) qd (with
pyridoxine 40 mg qd) +
– Ethambutol 15-25 mg/kg (maximum 1.6 gm) qd +
– PZA 15-30 mg/kg (maximum 2 gm) qd +
– Rifampin 10-20mg/kg (maximum 600 mg) qd
• Followed by maintenance phase for ≥ 4 months
– INH + Rifampicin

32. Con’t
• New patient regimen: 2(RHZE)/4(RH) total of 6 mths
– New TB pts
– Other previously treated pts smear –ve PTB and
EPTB cases (case definition “other”) who were
previously cured or Rx completed will be treated
new TB pt regimen
• Previously treated regimen:
2S(RHZE)/1(RHZE)/5(RH)E total of 8 mths
– Previously treated cases: other previously treated
cases with unfavorable treatment outcome or
unknown outcome of their most recent TB Rx

33. Con’t
 Common adverse effects of anti-TB drugs
• Ethambutol (EMB)
– Dose related ocular toxicity, GI intolerance
• Pyrazinamide (PZA)
– Hepatotoxicity, hyperuricemia, GI intolerance
• Isoniazid (INH)
– Hepatotoxicity, peripheral neuropathy, GI
intolerance
• Rifampin (R)
– Orange-brown discoloration, hepatotoxicity
• Streptomycin (SM)
– Ototoxicity, vestibular dysfn, rash, renal damage

34. Evaluating Response to Treatment
• Assess pt’s response to Rx using 3 methods:
– Clinical evaluation, bacteriological examination,
chest radiograph
• Conduct clinical evaluations at least monthly;
after 2 months of therapy, if symptoms do not
resolve, re-evaluate for:
– Potential drug-resistant disease
– Non-adherence to drug regimen

35. Con’t
• Bacteriological examination
– If cultures do not convert to -ve after 3 months of
therapy, evaluate pt for drug resistance or
adherence issues; after 4 months, consider
treatment failed
• Chest radiograph
– Pts with initially -ve cultures should have chest x-
ray after 2 months of treatment and at completion
of therapy.

36. Con’t
• Monitor for adverse reactions
• Common adverse reactions include
– Gastrointestinal problems
– Hepatitis
– Rash
– Fever

37. Treatment of Drug Resistant TB

38. Classification of drug- resistant TB
• Primary resistance: TB infection with resistant strain.
– If DST done before the start of patient’s first anti-
tuberculosis treatment, any resistance documented is
primary resistance
• Secondary or acquired resistance: TB infection
with susceptible strain which became resistant due to
inadequate treatment.
– If new resistance is found when DST is later repeated
and genetic testing confirms that it is the same strain,
only then can it be concluded that the strain has
acquired resistance

39. Preferred classification
• Resistance in new tuberculosis patients
 those never treated or treated for less than one
month.
• Resistance in previously treated patients
those previously treated with anti-TB drugs for more
than one month.

40. Resistance definitions
• Mono resistance: resistance to single anti-TB medicine
• Poly-resistance:
– resistance to more than one anti-TB medicine other than
Rifampicin and Isoniazid together
• Multi-Drug Resistance (MDR): resistance to at least Isoniazid
and Rifampicin
• Extensive drug resistance (XDR): MDR plus Resistance to:
– A fluoroquinolone : Ciprofloxacin, Ofloxacin, Levofloxacin,
Moxifloxacin, Gatifloxacin, etc
– One or more of the following injectable agents: Kanamycin,
Amikacin, Capreomycin
• Total drug-resistance (TDR-TB): resistance to all anti TB
medicines.

41. • Standardized or individualized
• All patients - at least 4 effective drugs
• Adequate use of injectable agent (at least 6
months., usually 6 months. past conversion)
• Adequate duration of treatment (no less than 18
months. past conversion; usually 24 months.
total)
Appropriate treatment regimens

42. 1. Oral first line drugs
2. Injectable drugs
3. Quinolones
4. Oral 2nd-line drugs
5. Third line dugs
As many as possible
One from each group
As many as needed (to get
≥ 4 effective)
In desperate cases (< 4
effective drugs)
Clear guidelines for designing regimens should
result in rational, consistent treatment

43. Treatment of MDR-TB
• Objectives
– Cure the TB patient and restore quality of life and
productivity
– Prevent death from active TB or its late effects
– Prevent TB relapse
– Prevent the development and transmission of extensive
medicine resistance
– Decrease transmission
• Non pharmacologic
– Adherence counselling
– Psychosocial and emotional support
– Nutritional support
– Admission of severe cases

44. Pharmacologic
• MDR-TB Patients with strains resistant to at least Rifampicin
and Isoniazid are treated with standardized 2nd line
treatment regimen for at least 18-24 months
• Medicine Resistance Survey (DRS) data from representative
patient populations are used to design a standardized
treatment regimen