A clinical overview of tuberculosis

1. TUBERCULOSIS
CLINICAL PHARMACY
Feroz Khan

2. Outline
• What is Tuberculosis (TB)?
• Types of TB
• How is it caused & transmitted?
• Epidemiology
• Symptoms
• Diagnosis
• Treatment
• ADR monitoring
• Chemoprophylaxis
• BCG vaccine
• Patient Care
• How can a pharmacist be of value?
• References

3. WHAT IS TUBERCULOSIS?

4. • Tuberculosis (TB) is an infection of cells of the body by notorious bacteria
belonging to the family Mycobacteriaceae.
• You should remember this family from your 2nd year Micro. If not, these
highly useful textbooks can help!

5. • This family includes the very famous bacteria Mycobacterium tuberculosis
and Mycobacterium leprae (the cause of leprosy), and many other
mycobacteria, about 15 of which cause disease in humans (TB-like
disease).
• Once introduced into the body, the bacteria cause an inflammatory
response, which now creates problems for the patient!
• Mycobacteria cause chronic inflammation, which means that the body’s
defense cells recognize these foreign bacteria, and surround them in an
attempt to destroy them.
• This results in caseous (cheese-like) necrosis in the affected tissue.

6. • This type of inflammation results in granuloma formation.
Gross section Microscopic view

7. Again, you should remember this type of chronic inflammation from your
3rd year Patho. This textbook may be valuable for further reading:

8. • These lesions commonly heal leaving no residual changes, except occasional
pulmonary or tracheobronchial lymph node calcification.
• Around 5% of those initially infected will develop active primary disease
(pulmonary TB or extra-pulmonary TB).
• In the other 95%, primary lesions heal without primary intervention, but in at
least one-half, bacilli survive in a latent form (LTBI), which may reactivate later
in life.
• After treatment, relapse may arise from exogenous reinfection or endogenous
reactivation.
• If untreated, about 65% of the patients will die within 5 years, the majority of
these within 2 years.
• Infants, adolescents & the immunocompromised are more susceptible to the
more serious forms of TB (miliary or meningeal TB).

9. TYPES OF TUBERCULOSIS
TB can generally be classified into
PULMONARY TB and EXTRAPULMONARY TB (EPTB)
This is TB infection This is TB infection of tissues
of the lung tissue. OTHER than the lung tissue.

10. Pulmonary TB

11. Extrapulmonary TB
• TB, like cancer, can virtually affect ANY part of the body. Some major
types include:
1) TB of peripheral lymph nodes
2) Bone & joint TB (most commonly the spine)
3) Meningeal TB
4) Disseminated/generalized/miliary TB
5) Pericardial TB
6) Cutaneous TB
7) Choroidal tubercles (TB infection of the eye!)

12. CUTANEOUS TB POTT’S DISEASE

13. TB OF CERVICAL LYMPH NODES CHOROIDAL TUBERCLES

14. HOW IS TB CAUSED & TRANSMITTED?
• Tuberculosis is typically caused by Mycobacterium tuberculosis (tubercle
bacilli). This is the TB we all know about!
• Atypical mycobacteria or non-tuberculous mycobacteria (NTM) , such as
M. kansasii, M. abscessus, M. africanum, M. bovis, M. avium, &
M. intracellulare cause TB-like disease, called atypical tuberculosis.
• M. avium & M. intracellulare are collectively called the Mycobacterium avium
Complex (MAC), and mostly cause infection in HIV +ve or AIDS patients.
• A comprehensive list of all mycobacterial species is given at:
http://en.wikipedia.org/wiki/Mycobacterium

15. • All mycobacteria are acid-fast bacilli (AFB), as they are not stained by
Gram staining, like most other bacteria. To see mycobacteria under the
microscope, we use a special staining procedure known as Ziehl-Neelsen
or acid-fast staining.

16. How to stain mycobacteria

17. This is how AFB appear under the microscope:
Acid-Fast Bacilli

18. • A viva tip: Nocardia species are also stained by acid-fast staining, so they
are also included in the spectrum of Acid-Fast Bacilli (AFB)!

19. TRANSMISSION OF TB

20. • It is important to note that only the respiratory forms of TB & laryngeal
TB are contagious, which means that the disease can be passed on from
an infected individual to an uninfected individual!
• TB cannot be acquired from individuals with latent TB infection (LTBI).
• Between 90-95% of cases of TB in children are non-infectious.
• Patients should be considered infectious if they have sputum smear-
positive pulmonary TB or laryngeal TB.

21. DROPLET INFECTION
AN INFECTED INDIVIDUAL SNEEZES/COUGHS A HEALTHY INDIVIDUAL INHALES DROPLETS

22. EPIDEMIOLOGY OF TB

23. SYMPTOMS
WHAT PROBLEMS DOES THE PATIENT EXPERIENCE IN TB?
• Patients only seek medical help when they notice that something is
wrong with them, for example they have fever, they cough too much, they
produce sputum with blood, they're losing weight, or they don't have
appetite for food!

24. • Symptoms of pulmonary TB caused by M. tuberculosis are discussed here,
since this is the most common type of TB you’ll see in hospitals. Also,
foreign licensure exams particularly focus on this type of TB, as it’s
common!
• Other types of TB require specialist treatment and different drug
regimens based on drug susceptibility testing (DST), i.e. we find out which
antibiotics will kill a given bacterium.

25. Incubation period
• Once M. tuberculosis enters the lungs, it takes about half a month to
2 months (2-10 weeks) to produce symptoms of disease, because it’s a
lazy, slow-growing bacterium!

26. Symptoms of pulmonary TB
FEVER WITH NIGHT SWEATS (MAY BE ABSENT) PRODUCTIVE COUGH FOR 3 WEEKS OR MORE
(MAY BE DRY)

27. MUCOPURULENT OR PURULENT SPUTUM HEMOPTYSIS (BLOOD IN SPUTUM; NOT ALWAYS A FEATURE)

28. • Weight loss (variable)
• Anorexia (variable; the patient doesn’t feel hungry!)
• Tiredness/malaise

29. DIAGNOSIS OF TB
HOW DO PHYSICIANS FIND OUT THAT THE PATIENT REALLY HAS TB?
• When you’re ill, you go to see a doctor so that he may give you some
meds to make you well!

30. Doctors use the following tools for diagnosis:
1) History of the patient (the problems you tell the doctor)
2) Physical exam Once the doctor has listened to your story, he now tries
to find what’s wrong with you. A physical exam includes:

31. Physical exam
(i) INSPECTION the doctor observes you!

32. (ii) AUSCULTATION the doctor listens to your chest/abdomen with a
stethoscope

33. (iii) PALPATION the doctor presses on a part of your body, such as the
abdomen or chest

34. (iv) PERCUSSION the doctor puts his hand on your body, e.g. on your chest or
abdomen, and hits his finger placed on your body with the finger of the other hand &
listens carefully to the type of sound produced. It may be dull or resonant.

35. A doctor may use all or just a few of the above to find out what’s wrong
with you!
3) Lab tests: Once the physician has an idea of what's wrong with the
patient, he advises some lab tests to confirm his diagnosis. For
pulmonary TB, these typically include:

36. (i) CBC with ESR
White cell count & ESR increase
in infections.

37. (ii) a chest X-ray (radiograph) or high-resolution (good quality) CT
scan, commonly called HRCT
Normal chest radiograph/X-ray Lungs show bilateral granuloma formation

38. HRCT SCAN OF THE THORAX (LUNGS SHOW PULMONARY TB)

39. (iii) check your sputum for the presence of AFB
3 sputum samples are tested, one of which should be taken early in the
morning.
WHAT DO THE LAB PEOPLE DO WITH YOUR SPUTUM?
put a sample of your sputum on a culture some sputum strain-typing of the
microscope slide, stain it using the containing ANY bacteria bacteria using
Ziehl-Neelsen staining method on a media to see its growth sophisticated techniques,
(discussed before) and observe under & drug-susceptibility testing such as PCR. GeneXpert,
the microscope (DST) MIRU/VNTR are examples.
(Lowenstein-Jensen media takes
6 weeks)

42. • PRESENCE OF AFB IN YOUR SPUTUM MEANS YOU HAVE PULMONARY TB
& WE CAN START TREATMENT RIGHT AWAY WITHOUT ANY FURTHER
TESTS!
• BUT MOST PHYSICIANS ALSO ADVISE A MANTOUX TEST AT THE SAME
TIME THEY ASK YOU TO GET YOUR SPUTUM CHECKED FOR AFB.

43. (iv) get a skin test done (Mantoux test or tuberculin skin testing/TST)
When mycobacteria enter your body, an immune response takes place
& plasma cells produce antibodies against the bacteria. Mantoux test is
used to detect the presence of such antibodies in your blood.
• Intradermal (ID) injection of 2 test units (TU) of Statens Serum Institute
(SSI) tuberculin RT23 in 0.1 mL solution is given on the forearm to
produce a bleb of around 7mm.
• The results are observed 48-72 h later (up to 96 h).
• Sometimes called the PPD (purified protein derivative) test.

44. ID INJECTION OF TUBERCULIN GIVEN INFLAMMATION OCCURS
THE SIZE IS MEASURED

45. POSITIVE MANTOUX TEST (CH&ICH)

46. Interpretation of Mantoux test
• Diameter < 6mm is –ve
• 6-15mm: in the absence of specific risk factors, it is suggestive of previous
TB infection, BCG vaccination or non-tuberculous bacteria.
• > 15mm: strongly suggestive of active TB infection

47. Quick review of investigations
1) CBC with ESR
2) CXR +/- HRCT scan
3) Sputum for AFB, culture, DST and strain typing
4) Mantoux test/Tuberculin test/PPD test
• These tests are usually enough and help the physician what to do next.
However, sometimes other tests may be needed when the tests above fail
to present a clear picture:

49. (v) Fine-needle aspiration, commonly called FNA (they use a needle to take
a sample of the infected tissue)
(vi) biopsy (they may excise a whole lymph node or part of the tissue to
observe it under the microscope)
CLINICAL PEARL:
• It is possible for a TB patient to have a normal or close to normal CBC,
ESR, CXR, with no AFB seen in sputum, and a –ve mantoux test. Even the
results of FNA may be –ve. TISSUE BIOPSY, HOWEVER, IS CONFIRMATORY!

50. CLINICAL PEARL:
• If the results of all investigations do not help the physician to decide, yet
he has strong suspicion that the patient has TB, the specialist/consultant
may begin anti-TB treatment (ATT) on trial! If the symptoms of the
patients begin to subside once ATT has been started and the patient has
no other co-morbidity, diagnosis of TB is confirmed.

51. TREATMENT OF TB
• Once the physician knows you have TB, he puts you on meds to make you
well!
• Mycobacteria are stubborn bacteria and do not die easily.
• They are clever, and when you try to kill them with an antibiotic, they
develop resistance against the antibiotic and keep multiplying just to
make you feel worse.
• Hence, over the years, some intelligent health-care professionals have
come up with a fantastic idea of treating TB patients with more than one
anitbiotic at a time. We usually use 4 drugs, namely:

52. 1) RIFAMPIN (ALSO CALLED RIFAMPICIN)
2) ISONAZID
3) PYRAZINAMIDE
4) ETHAMBUTOL
• A tip to learn these names is the mnemonic RIPE.
• Rifampin, isoniazid & pyrazinamide are bactericidal whereas ethambutol
is bacteriostatic.
• Combination drug therapy delays emergence of resistance and has a
synergistic effect against MT.

53. • Since MT are stubborn and robust bacteria, they do not die easily &
prolonged treatment is required for about 6 months usually.
• The treatment is divided into the initial phase (or intensive phase) & the
continuation phase.

54. • Being drug experts, you pharmacists should be familiar with the
pharmacology of these drugs. That includes:
 their mechanism of action
 their pharmacokinetics
 their doses in different populations, ages, in patients taking other drugs
 their ADRs
 their drug-drug interactions
 their drug-food interactions
 dosage forms available
 famous or commonly used brands

55. • These references may be useful:

56. Classification & dosing of anti-TB drugs
• 1st line agents:
Drug Dose
Adults daily
Dose
Adults intermittent (doses per
week)
RIFAMPIN 45Omg (<50 kg)
600mg (>50 kg)
15mg/kg (3 doses/week)
ISONIAZID 300mg 15mg/kg (3 doses/week)
PYRAZINAMIDE 1.5g (<50 kg)
2.0g (>50 kg)
2.0g (<50 kg) 3 doses/week
2.5g (>50 kg)
ETHAMBUTOL 15 mg/kg
STREPTOMYCIN 750mg (<50 kg)
1g (>50 kg)
750mg-1g

57. DOT
• Since treatment of TB is prolonged, people often forget to take their
meds, or may discontinue treatment as they are ignorant of the damage
the disease can cause them.
• Hence, we often put such patients on intermittent therapy known as
DIRECTLY OBSERVED TREATMENT (DOT) in a hospital. In DOT, patients
take their meds only thrice a week instead of daily dosing.

58. Drug abbreviations
• Since we healthcare professionals are busy people, we often use abbreviations
to denote TB drugs.
• Rifampin- RIF
• Isoniazid- INH
• Pyrazinamide- PZA
• Ethambutol- EMB
• Sometimes, we also use the letters EHRZ (Ethambutol, Isoniazid, Rifampin,
Pyrazinamide). Numbers with these letters represent no. of tablets or doses.

59. It’s important you learn their doses!

60. What you might see in hospitals!

61. Children’s Hospital Lahore OPD Pharmacy

64. Use of Pyridoxine (vitamin B6)
• Isoniazid may cause peripheral neuropathy: the patient has a tingling
sensation in his finger tips or toes.
• Hence, we give 25-50mg of pyridoxine to patients taking isoniazid, as it
helps prevent neuropathy.

66. A real patient’s prescription!

67. 2nd line drugs
• First-line drugs are always preferred as they are highly efficacious & have a better
side-effect-profile than most 2nd line drugs.
• We need 2nd line drugs when patients do not respond to 1st line agents as the
bacteria may be resistant.
• Sometimes, patients cannot tolerate the ADRs of some 1st line drugs and we have to
put them on other meds to cure their TB!

68. Common 2nd Line Drugs Dose in adults
Amikacin 15mg/kg
Capreomycin 15mg/kg
Kanamycin 15mg/kg
Ethionamide or prothionamide 375mg BD (<50kg)
500mg BD (>50kg)
Thiacetazone 150mg
Cycloserine 250-500mg BD
Ofloxacin 400mg BD
Ciprofloxacin 750mg BD
Azithromycin 500mg OD
Clarithromycin 500mg BD
Clofazimine 300mg
Rifabutin 300-450mg
PAS sodium 10g every morning or 5g BD

69. Be good pharmacists!
• Being pharmacists, you should know the dosing of all these drugs in different types
of patients and how to change drugs or doses in pregnancy, breastfeeding, hepatic
or renal impairment, or in a patient with other diseases and drugs.

70. These references can help!

71. CHEMOPROPHYLAXIS AGAINST TB
• Used in patients with LTBI to help prevent active TB.
• We use either ISONIAZID alone for 6 months or a combo of ISONAZID +
RIFAMPIN for 3 months!

72. BCG VACCINE
• BCG stands for Bacillus Calmette–Guérin.
• This vaccine contains a live, attenuated strain of M. bovis.
• The BCG vaccine does not prevent TB, as most people think, but it
protects against the more serious forms of disease such as miliary TB or
meningeal TB.

73. PATIENT CARE
• Factors affecting adherence
• Improving patient adherence (multi-drug brands)
• Information for patients/educating patients
• DOT
• Counseling patients

74. HOW CAN PHARMACISTS BE OF VALUE?
• Dosing
• Medication therapy management (MTM)
• ADR monitoring
• Patient counseling
• Help chose 2nd line drugs
• The concept of pharmaceutical care

75. LEGAL ACTION AGAINST TB
• In the UK and most other developed countries, TB is an officially
notifiable disease, which means that whenever we diagnose a patient
with TB, we notify the local health officer.
• They usually conduct contact tracing to find out the source of infection.

76. • Patients with too many AFB in their sputum (the lab reports it as +++) are
highly infectious to others, and we might consider hospitalizing them to
save family at home from contracting TB. Sometimes negative pressure
rooms in hospitals are used.
• Health care professionals treating such patients really need to be careful
and ask the patients to wear a mask.

77. • In the UK & most developed countries, if such infected patients are non-
cooperative with us and do not want to get admitted into the hospital, we
can even get a court order to institutionalize/hospitalize them!

84. REFERENCES
1. Clinical Pharmacy & Therpautics, Roger Walker, Cate Whittlesea, 5th ED.
2. Clinical Microbiology Made Ridiculously Simple, Mark Gladwin, Bill Trattler, 5th ED.
3. Rapid Review Pathology, Edward F. Goljian, 3rd ED.
4. British National Formulary (BNF) 64, September 2012
5. Therapeutic Choices, Canadian Pharmacist’s Association, 6th ED.
6. Global Tuberculosis Report 2013, World Health Organization
7. Lippincott’s Illustrated reviews: Pharmacology, Richard A. Harvey, 4th ED.
8. Photographs taken while I interned at the CH&ICH, Lahore.
9. www.google.com
10. www.wikipedia.org

85. THANK YOU FOR YOUR ATTENTION!