Tuberculosis Drugs Flashcards
How many individuals died of TB infection in 2015?
1.8 million
How many individuals died of MDR in 2016?
240,000
XDR has been observed in how many countries?
117 countries
How many individuals were infected with TB in 2015?
10.4 million
Why is TB increasing in the UK?
- Immigration
- Drug resistance
- Worldwide travel
- HIV co-infection
When was the first TB antibiotic identified, what was it?
Streptomycin 1943
What are symptoms of TB infection?
- Chills
- Coughing for over 3 weeks
- Coughing up blood
- Fever
- Night sweats
- Unintentional weight loss
- Chest pain
- Difficulty breathing
How can TB be diagnosed?
- Mantoux TST
- Chest X-ray
- Alere Determine TB LAM Ag
- IGRA: QuantiFERON TB Gold
- Sputum smear microscopy
- 16S rRNA probes
TST results can be obtained within?
48-72 hours
Sputum smear microscopy results can be obtained within?
3-6 weeks
Chest X-ray results can be obtained within?
Immediately
IGRA results can be obtained within?
24 hours
What is IGRA?
Interferon Gamma Release Assay
Main issue with TST?
False positives due to BCG vaccination
Which test is not impacted by BCG vaccination?
Interferon gamma release assay
Main issues with chest X-ray?
X-ray exposure is not ideal
Can only identify the late stages of infection
16S rRNA is associated with?
30S ribosomal subunit
Prokaryotic ribosome structure?
30S small subunit
50S large subunit
70S ribosome
16S rRNA structure?
Has conserved regions
Has variable regions which are species/genus specific
How can 16S rRNA be used to identify bacteria?
- Primers to the conserved regions which amplify the variable regions
- Compare the sequence of the variable regions to known sequence databases
What is used to stimulate the T cell IFN-g production in vitro in the interferon gamma release assay?
CFP-10
TB 7.7
ESAT-6
What can detect IFN-G in the IGRA?
ELISA technology
Why does is QuantiFERON TB Gold not impacted by BCG?
As attenuated mycobacterium bovis has an RD1 deletion which means it lacks the CFP-10 and ESAT-6
Can IGRA distinguish between latent and active infection?
No
Can Mantoux TST distinguish between latent and active infection?
No
What are we looking for in an effective diagnosis?
- 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
Why can LAM be detected in the urine of HIV+ TB co-infected individuals?
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
What were the earliest TB treatments?
Purple bugle to encourage individuals to cough up blood
TB sanatoriums
When was the first TB drug identified and what was it?
WWII
1943
Streptomycin
DOTS is?
Directly Observed Treatment, short course
DOTS is how long?
6 months
2 months with?
Rifampicin, isoniazid, pyrazinamide and ethambutol
4 months with?
Rifampicin and isoniazid
Which drugs are cell wall synthesis inhibitors?
Isoniazid and ethambutol
Which drugs are prodrugs?
Isoniazid and pyrazinamide
Which drug can penetrate into the caseum?
Pyrazinamide
Which drug stays in the rim of the granuloma?
Clofazimine
What does isoniazid do?
Prevents mycolic acid synthesis
What does ethambutol do?
Inhibits arabinosyl transferases
Prevents arabinogalactan synthesis
What does pyrazinamide do?
Energy inhibitor
De-energises the membrane
Collapses the proton motive force
What does streptomycin do?
Protein synthesis inhibitor
Blocks 30S ribosomal subunit and associated 16S rRNA
What do fluoroquinolones do?
DNA synthesis inhibitor, inhibits DNA gyrase and topoisomerase IV activity
What does bedaquiline do?
ATP synthase inhibitor
Promising new drug?
Bedaquiline
What is required to activate isoniazid prodrug?
KatG
Catalase peroxidase
What is required to activate pyrazinamide prodrug?
Pyrazinamidase
What encodes catalase peroxidase?
katG gene
What encodes pyrazinamidase?
pncA gene
Resistance to isoniazid?
Overexpression of InhA
Mutations in katG or inhA genes
Resistance to pyrazinamide?
Mutations in pnca
Resistance to ethambutol?
Mutations in arabinosyl transferases
Resistance to rifampin?
Mutations in rpoB
rpoB gene?
DNA dependent RNA polymerase
Rifampin action?
Prevents transcription by inhibiting the DNA dependent RNA polymerase
Resistance to streptomycin?
Mutations in the 16S rRNA gene
Resistance to fluoroquinolones?
Mutations in the DNA gyrase
How does pyrazinamide work?
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
What are drug tolerant bacteria?
These are persisters
They have phenotypic resistance
What is phenotypic resistance?
Same genome as susceptible cells but able to tolerate certain levels of antibiotics
What can drive phenotypic resistance?
The lack of vascularisation in the caseum
Low nutrients and low oxygen can cause cells to become metabolically inactive and dormant
Many antibiotics rely on cells being?
Metabolically active
Which antibiotic is ineffective on dormant cells?
Isoniazid
Which type of resistance is genetic?
MDR and XDR
Types of genetic resistance?
Natural intrinsic
Acquired
Why is combination therapy required?
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
