Tuberculosis Chemotherapy

Question 1

What is the current 1st line treatment for TB?

Answer 1

RIPE for 6 months DOTS

Question 2

What is the intensive phase of TB treatment?

Answer 2

2 months of RIPE

Question 3

What is the continuation phase of TB?

Answer 3

4 months rifampicin and isoniazid

Question 4

How long is the treatment for drug-resistant TB?

Answer 4

1-2 years

Question 5

What is 1st line for drug resistant TB?

Answer 5

fluoroquinolones

Question 6

What is 2nd line for drug-resistant TB?

Answer 6

aminoglycosides; thiamines

Question 7

Why is such a long course of treatment for TB needed?

Answer 7

cells are able to enter into a dormant state as persisters - drugs target active processes

Question 8

What is resistance?

Answer 8

ability of bacteria to survive the presence of a drug at a conc. that normally kills or inhibits growth

Question 9

What is natural resistance?

Answer 9

non-susceptibility due to bacterial cell characteristics

Question 10

Give an exmaple of natural resistance?

Answer 10

Mtb expresses a beta-lactamase so is naturally resistant to penicillin

Question 11

What is acquired resistance?

Answer 11

non-susceptibility due to genotypic change

Question 12

What are the mechanisms of resistance?

Answer 12

target modification; target over-expression; drug-inactivating mechanisms; barrier mechanisms (influx and effflux); plasmid-mediated resistance

Question 13

Why does drug resistance occur?

Answer 13

non-compliance; incomplete drug regimen; sub-optimal dosage; poor drug absorption

Question 14

What is the target for RIF?

Answer 14

RNA polymerase enzyme

Question 15

What is the MOA of RIF?

Answer 15

inhibits DNA transcription by binding to the RNA polymerase enzyme, blocking exit channel preventing the production/exit of mRNA from DNA

Question 16

What is the most common mutation resulting in RIF resistance?

Answer 16

RNA polymerase beta sub-unit rpoB gene- prevents binding of drug to enzyme

Question 17

What does INH require activation by?

Answer 17

catalase peroxidase

Question 18

What encodes catalase peroxidase?

Answer 18

katG gene

Question 19

What is the action of active INH?

Answer 19

generates a range of radicals which target mycolic acid syntehsis; NAD metabolism; oxidative stress response

Question 20

Give an example of INH mutation causing resistance?

Answer 20

katG preventing binding and activation of INH

Question 21

When is PZA active?

Answer 21

after activation by pyrazinamidase enzyme and at acidic pH

Question 22

What is the active form of PZA?

Answer 22

pyrazinoic acid

Question 23

What is the general mechanism of PZA?

Answer 23

destabilises the TB membrane using proton motive force3

Question 24

What is the major cause of PZA resistance?

Answer 24

mutations in the pro-drug activating PZase pncA gene

Question 25

What is the MOA of EMB?

Answer 25

inhibits cell wall arabinogalactan synthesis by blocking arabinosyl transferase

Question 26

What is arabinogalactan?

Answer 26

major polysaccharide in cell wall

Question 27

What is the main mechanism of resistance to EMB?

Answer 27

mutations in embB- arabinosyl transferase

Question 28

What si hte MOA of fluoroquinolones?

Answer 28

inhibits DNA synthesis

Question 29

What causes resistance to fluoroquinolones?

Answer 29

mutations in DNA gyrase (gyrA and gyrB)

Question 30

What is the MOA of streptomycin?

Answer 30

inhibits mRNA translation in protein synthesis

Question 31

What causes resistance to streptomycin?

Answer 31

mutations in sequences encoding the ribosomal subunits

Question 32

Why do bedaquiline get a fast-track approval?

Answer 32

based on faster sputum conversion not clinical outcome

Question 33

When is bedaquiline used?

Answer 33

in MDR and XDR TB

Question 34

What is a problem with bedaquiline?

Answer 34

issues with QTc

Question 35

What is needed in terms of new drugs?

Answer 35

active in both MDR - TB and non-dividing cells(to shorten treatment times)

Question 36

What are the environmental conditions in a granuloma?

Answer 36

low carbon and oxygen concentrations

Question 37

Who should not receive fluoroquinolones?

Answer 37

pregnant women and young children

Question 38

What are the features of ideal TB drug targets?

Answer 38

should be required for bacterial growth and persistence; should be possible to inhibt their activty using small molecules and should be accessible to these modulatory compounds

Question 39

Waht is the structure of the mycobacterial cell wall?

Answer 39

layer of peptidoglycan then layer of arabinogalactan then mycolic acids with glyoclipids attached