Tuberculosis Chemotherapy Flashcards Preview

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Flashcards in Tuberculosis Chemotherapy Deck (39):
1

What is the current 1st line treatment for TB?

RIPE for 6 months DOTS

2

What is the intensive phase of TB treatment?

2 months of RIPE

3

What is the continuation phase of TB?

4 months rifampicin and isoniazid

4

How long is the treatment for drug-resistant TB?

1-2 years

5

What is 1st line for drug resistant TB?

fluoroquinolones

6

What is 2nd line for drug-resistant TB?

aminoglycosides; thiamines

7

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

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

8

What is resistance?

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

9

What is natural resistance?

non-susceptibility due to bacterial cell characteristics

10

Give an exmaple of natural resistance?

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

11

What is acquired resistance?

non-susceptibility due to genotypic change

12

What are the mechanisms of resistance?

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

13

Why does drug resistance occur?

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

14

What is the target for RIF?

RNA polymerase enzyme

15

What is the MOA of RIF?

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

16

What is the most common mutation resulting in RIF resistance?

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

17

What does INH require activation by?

catalase peroxidase

18

What encodes catalase peroxidase?

katG gene

19

What is the action of active INH?

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

20

Give an example of INH mutation causing resistance?

katG preventing binding and activation of INH

21

When is PZA active?

after activation by pyrazinamidase enzyme and at acidic pH

22

What is the active form of PZA?

pyrazinoic acid

23

What is the general mechanism of PZA?

destabilises the TB membrane using proton motive force3

24

What is the major cause of PZA resistance?

mutations in the pro-drug activating PZase pncA gene

25

What is the MOA of EMB?

inhibits cell wall arabinogalactan synthesis by blocking arabinosyl transferase

26

What is arabinogalactan?

major polysaccharide in cell wall

27

What is the main mechanism of resistance to EMB?

mutations in embB- arabinosyl transferase

28

What si hte MOA of fluoroquinolones?

inhibits DNA synthesis

29

What causes resistance to fluoroquinolones?

mutations in DNA gyrase (gyrA and gyrB)

30

What is the MOA of streptomycin?

inhibits mRNA translation in protein synthesis

31

What causes resistance to streptomycin?

mutations in sequences encoding the ribosomal subunits

32

Why do bedaquiline get a fast-track approval?

based on faster sputum conversion not clinical outcome

33

When is bedaquiline used?

in MDR and XDR TB

34

What is a problem with bedaquiline?

issues with QTc

35

What is needed in terms of new drugs?

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

36

What are the environmental conditions in a granuloma?

low carbon and oxygen concentrations

37

Who should not receive fluoroquinolones?

pregnant women and young children

38

What are the features of ideal TB drug targets?

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

39

Waht is the structure of the mycobacterial cell wall?

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