Tuberculosis Chemotherapy Flashcards
What is the current 1st line treatment for TB?
RIPE for 6 months DOTS
What is the intensive phase of TB treatment?
2 months of RIPE
What is the continuation phase of TB?
4 months rifampicin and isoniazid
How long is the treatment for drug-resistant TB?
1-2 years
What is 1st line for drug resistant TB?
fluoroquinolones
What is 2nd line for drug-resistant TB?
aminoglycosides; thiamines
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
What is resistance?
ability of bacteria to survive the presence of a drug at a conc. that normally kills or inhibits growth
What is natural resistance?
non-susceptibility due to bacterial cell characteristics
Give an exmaple of natural resistance?
Mtb expresses a beta-lactamase so is naturally resistant to penicillin
What is acquired resistance?
non-susceptibility due to genotypic change
What are the mechanisms of resistance?
target modification; target over-expression; drug-inactivating mechanisms; barrier mechanisms (influx and effflux); plasmid-mediated resistance
Why does drug resistance occur?
non-compliance; incomplete drug regimen; sub-optimal dosage; poor drug absorption
What is the target for RIF?
RNA polymerase enzyme
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
What is the most common mutation resulting in RIF resistance?
RNA polymerase beta sub-unit rpoB gene- prevents binding of drug to enzyme
What does INH require activation by?
catalase peroxidase
What encodes catalase peroxidase?
katG gene
What is the action of active INH?
generates a range of radicals which target mycolic acid syntehsis; NAD metabolism; oxidative stress response
Give an example of INH mutation causing resistance?
katG preventing binding and activation of INH
When is PZA active?
after activation by pyrazinamidase enzyme and at acidic pH
What is the active form of PZA?
pyrazinoic acid
What is the general mechanism of PZA?
destabilises the TB membrane using proton motive force3
What is the major cause of PZA resistance?
mutations in the pro-drug activating PZase pncA gene
What is the MOA of EMB?
inhibits cell wall arabinogalactan synthesis by blocking arabinosyl transferase
What is arabinogalactan?
major polysaccharide in cell wall
What is the main mechanism of resistance to EMB?
mutations in embB- arabinosyl transferase
What si hte MOA of fluoroquinolones?
inhibits DNA synthesis
What causes resistance to fluoroquinolones?
mutations in DNA gyrase (gyrA and gyrB)
What is the MOA of streptomycin?
inhibits mRNA translation in protein synthesis
What causes resistance to streptomycin?
mutations in sequences encoding the ribosomal subunits
Why do bedaquiline get a fast-track approval?
based on faster sputum conversion not clinical outcome
When is bedaquiline used?
in MDR and XDR TB
What is a problem with bedaquiline?
issues with QTc
What is needed in terms of new drugs?
active in both MDR - TB and non-dividing cells(to shorten treatment times)
What are the environmental conditions in a granuloma?
low carbon and oxygen concentrations
Who should not receive fluoroquinolones?
pregnant women and young children
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
Waht is the structure of the mycobacterial cell wall?
layer of peptidoglycan then layer of arabinogalactan then mycolic acids with glyoclipids attached
