Tuberculosis Drugs

Question 1

How many individuals died of TB infection in 2015?

Answer 1

1.8 million

Question 2

How many individuals died of MDR in 2016?

Answer 2

240,000

Question 3

XDR has been observed in how many countries?

Answer 3

117 countries

Question 4

How many individuals were infected with TB in 2015?

Answer 4

10.4 million

Question 5

Why is TB increasing in the UK?

Answer 5

• Immigration
• Drug resistance
• Worldwide travel
• HIV co-infection

Question 6

When was the first TB antibiotic identified, what was it?

Answer 6

Streptomycin 1943

Question 7

What are symptoms of TB infection?

Answer 7

• Chills
• Coughing for over 3 weeks
• Coughing up blood
• Fever
• Night sweats
• Unintentional weight loss
• Chest pain
• Difficulty breathing

Question 8

How can TB be diagnosed?

Answer 8

• Mantoux TST
• Chest X-ray
• Alere Determine TB LAM Ag
• IGRA: QuantiFERON TB Gold
• Sputum smear microscopy
• 16S rRNA probes

Question 9

TST results can be obtained within?

Answer 9

48-72 hours

Question 10

Sputum smear microscopy results can be obtained within?

Answer 10

3-6 weeks

Question 11

Chest X-ray results can be obtained within?

Answer 11

Immediately

Question 12

IGRA results can be obtained within?

Answer 12

24 hours

Question 13

What is IGRA?

Answer 13

Interferon Gamma Release Assay

Question 14

Main issue with TST?

Answer 14

False positives due to BCG vaccination

Question 15

Which test is not impacted by BCG vaccination?

Answer 15

Interferon gamma release assay

Question 16

Main issues with chest X-ray?

Answer 16

X-ray exposure is not ideal

Can only identify the late stages of infection

Question 17

16S rRNA is associated with?

Answer 17

30S ribosomal subunit

Question 18

Prokaryotic ribosome structure?

Answer 18

30S small subunit
50S large subunit
70S ribosome

Question 19

16S rRNA structure?

Answer 19

Has conserved regions

Has variable regions which are species/genus specific

Question 20

How can 16S rRNA be used to identify bacteria?

Answer 20

• Primers to the conserved regions which amplify the variable regions
• Compare the sequence of the variable regions to known sequence databases

Question 21

What is used to stimulate the T cell IFN-g production in vitro in the interferon gamma release assay?

Answer 21

CFP-10
TB 7.7
ESAT-6

Question 22

What can detect IFN-G in the IGRA?

Answer 22

ELISA technology

Question 23

Why does is QuantiFERON TB Gold not impacted by BCG?

Answer 23

As attenuated mycobacterium bovis has an RD1 deletion which means it lacks the CFP-10 and ESAT-6

Question 24

Can IGRA distinguish between latent and active infection?

Answer 24

No

Question 25

Can Mantoux TST distinguish between latent and active infection?

Answer 25

No

Question 26

What are we looking for in an effective diagnosis?

Answer 26

- Fast - High sensitivity - High specificity - Reliable - Cost effective - Safe - Easy to perform - Can be transportable - Not impacted by vaccination - Non-invasive - Can diagnose infection in children

Question 27

Why can LAM be detected in the urine of HIV+ TB co-infected individuals?

Answer 27

As they have a low CD4+ cell count, TB infection could not be contained, results in disseminated TB disease. LAM is shed by the bacteria in the kidneys and is released into the urine

Question 28

What were the earliest TB treatments?

Answer 28

Purple bugle to encourage individuals to cough up blood | TB sanatoriums

Question 29

When was the first TB drug identified and what was it?

Answer 29

WWII 1943 Streptomycin

Question 30

DOTS is?

Answer 30

Directly Observed Treatment, short course

Question 31

DOTS is how long?

Answer 31

6 months

Question 32

2 months with?

Answer 32

Rifampicin, isoniazid, pyrazinamide and ethambutol

Question 33

4 months with?

Answer 33

Rifampicin and isoniazid

Question 34

Which drugs are cell wall synthesis inhibitors?

Answer 34

Isoniazid and ethambutol

Question 35

Which drugs are prodrugs?

Answer 35

Isoniazid and pyrazinamide

Question 36

Which drug can penetrate into the caseum?

Answer 36

Pyrazinamide

Question 37

Which drug stays in the rim of the granuloma?

Answer 37

Clofazimine

Question 38

What does isoniazid do?

Answer 38

Prevents mycolic acid synthesis

Question 39

What does ethambutol do?

Answer 39

Inhibits arabinosyl transferases | Prevents arabinogalactan synthesis

Question 40

What does pyrazinamide do?

Answer 40

Energy inhibitor De-energises the membrane Collapses the proton motive force

Question 41

What does streptomycin do?

Answer 41

Protein synthesis inhibitor | Blocks 30S ribosomal subunit and associated 16S rRNA

Question 42

What do fluoroquinolones do?

Answer 42

DNA synthesis inhibitor, inhibits DNA gyrase and topoisomerase IV activity

Question 43

What does bedaquiline do?

Answer 43

ATP synthase inhibitor

Question 44

Promising new drug?

Answer 44

Bedaquiline

Question 45

What is required to activate isoniazid prodrug?

Answer 45

KatG | Catalase peroxidase

Question 46

What is required to activate pyrazinamide prodrug?

Answer 46

Pyrazinamidase

Question 47

What encodes catalase peroxidase?

Answer 47

katG gene

Question 48

What encodes pyrazinamidase?

Answer 48

pncA gene

Question 49

Resistance to isoniazid?

Answer 49

Overexpression of InhA | Mutations in katG or inhA genes

Question 50

Resistance to pyrazinamide?

Answer 50

Mutations in pnca

Question 51

Resistance to ethambutol?

Answer 51

Mutations in arabinosyl transferases

Question 52

Resistance to rifampin?

Answer 52

Mutations in rpoB

Question 53

rpoB gene?

Answer 53

DNA dependent RNA polymerase

Question 54

Rifampin action?

Answer 54

Prevents transcription by inhibiting the DNA dependent RNA polymerase

Question 55

Resistance to streptomycin?

Answer 55

Mutations in the 16S rRNA gene

Question 56

Resistance to fluoroquinolones?

Answer 56

Mutations in the DNA gyrase

Question 57

How does pyrazinamide work?

Answer 57

Transformed into pyrazinoic acid by pyrazinamidase In acid pH the uncharged protonated pyrazinoic acid can cross the membrane along with protons, this can de-energise the membrane and lead to collapse of the proton motive force

Question 58

What are drug tolerant bacteria?

Answer 58

These are persisters | They have phenotypic resistance

Question 59

What is phenotypic resistance?

Answer 59

Same genome as susceptible cells but able to tolerate certain levels of antibiotics

Question 60

What can drive phenotypic resistance?

Answer 60

The lack of vascularisation in the caseum | Low nutrients and low oxygen can cause cells to become metabolically inactive and dormant

Question 61

Many antibiotics rely on cells being?

Answer 61

Metabolically active

Question 62

Which antibiotic is ineffective on dormant cells?

Answer 62

Isoniazid

Question 63

Which type of resistance is genetic?

Answer 63

MDR and XDR

Question 64

Types of genetic resistance?

Answer 64

Natural intrinsic | Acquired

Question 65

Why is combination therapy required?

Answer 65

No single antibiotic in our current arsenal can penetrate every area of the granuloma and target all the different types of bacteria present To prevent resistance developing