Fan - Antimycobacterial Therapies Flashcards
Under what circumstances are second line TB drugs used?
- multi drug resistant TB - resistance to isoniazid and rifampin
- extensively drug-resistant TB - MDR +. Resistanc to Fluoroquinoolones and inject isle Aminoglycosides
- first line is too toxic
What parts of mycobacterium are unique, which allow us to target them? What do we use to target them?
Mycolate - inhibited by isoniazid (INH)
Arabinogalactan - inhibited by ethambutol (EMB)
What do each of the first line TB drugs do?
Rifampicin - inhibits RNA synthesis by target RNA Polymerase
Pyrazinamide - inhibits protein synthesis in dormant bacteria
Isoniazid - inhibits mycolic acid synthesis
Ethambutol - inhibits cell wall synthesis by targeting arabinogalactan synthesis
How do we initially treat TB???
Start With all 4 first line treatment.
- if the patient can cough up some sputum for us to to genome sequencing then we can narrow down which drugs to use.
- Otherwise, it takes 3-8 weeks to identify resistant strains.
Mechanisms of drug resistance
Genetic mechanism - natural resistance due to chromosomal mutation
Biochemical mutation - over expressed drug target, decreased drug binding, increased drug removal, deficiency in pro-drug activation.
Why are insufficient drugs so bad?
The create an environment that gives all of the resources to the microbes that are most resistant and then they grow.
If bacteria are culture-positive, how do we treat them?
So, after the 8 weeks are up and we can figure out what we are working with, we scale back the 4 drugs and only use 2.
- use for either 6 or 9 months.
If bacteria are culture-negative how do we treat them?
Again we treated for 8 weeks with the 4 drugs and then treat for 2 more months with INH and RIF
Why do we do multi-drug therapy?
For INH you have 1 spontaneous resistant per 1,000,000 bacteria. In TB lesion you have about 100,000,000 bacteria. So, even before treatment you would have 100 bacteria that are resistant. That 100 though can now take all of the resources and dominate. Rifampin is better than INH in this regards because only 1/100,000,000 will have spontaneous resistance. But that leaves 1 that will take the resources and Dominate. If we combine the two then you will be highly unlikely to have any resistant microbes. This is why we start with 4 drugs usually.
Challenges in treating. TB
- very slow growing Infection - bacteria can hide in macrophages and wait until immunosuppression occurs and then they break out and make moves.
- MT readily accumulate mutations that cause drug resistance
- doctor and patient compliance - long treatment (6-9 months)
- lipid-rich cell wall - provides protection from many antibiotics.
- HIV/AIDS often coexist with TB
Isoniazid
Pro-drug that is activated by bacterial KatG.
- KatG oxidizes the INH to form double bonds.
- this ionized form then combines with NAD to make the active form of the drug.
- inhibits mycolic synthesis.
Mechanism of action of isoniazid
Mycolic acid has a long chain and a short chain that are both synthesized by FAS-I (for the short parts) and FAS-II (for the longer part). They then come together to form the cell wall.
- INH targets the FabI step of biosynthesis. INH has a higher affinity for the NADH than does FabI, so biosynthesis of mycolic acid does not proceed.
Adverse effects of isoniazid
Hepatitis (varies with age, it is safer the younger you are)
Peripheral neuropathy
Why is peripheral neuropathy a side effect of isoniazid?
Because isoniazid looks a whole lot like Vitamin B6, so you would have a pyridoxine deficiency.
- give pyridoxine when you give this drug.
Resistance to INH?
- mutations in KatG so INH can’t be formed
- mutations in NADH binding pocket of Fab1 that reduce affinity for INH
- mutations that increase expression of Fab1
- mutations that cause elevated NADH, which outcompeted INH-NAD for Fab1
Rifampin
Inhibits RNA synthesis
RIfampin mechanism of action
- prevents RNA exit from polymerase by interacting with large subunit of bacterial polymerase and directly blocking the path of the growing RNA
- blocks departure of bacterial RNA polymerase from gene promoters.
- human RNA polymerase do not bind rifampin.
Rifampin resistance
Resistance arises from mutations in the gene encoding the beta-subunit of RNA Polymerase so that they don’t bind the drug.
Adverse effects of rifampin
- May cause flu-like symptoms
- induces Cytochrome P450 members including CYP3A, which causes elimination of other drugs
- can cause hepatitis
- can give purple or red color urine, sweat, or tears
What added benefits do the derivatives of rifampin have?
- Higher potencies
- longer half lives
- better membrane permeability
- less active in CYP3A induction so it has better compatibility with other meds
Pyrazinamide
- looks similar to INH but acts differently.
- also a pro-drug
- if Pyrazinamide is used in treatment, treatment can be shortened to 6 months instead of 9.
Mode of action of PZA?
Not exactly sure of the mechanism but we now that it doesn’t t affect the cell wall synthesis. It might have multiple modes, one might be inhibition of trans-translation. The other might be inhibition of pantothenate and CoA synthesis.
Ethambutol
Inhibits biosynthesis of arabinogalactan. It blocks the EmbA and EmbB arabinotransferases that incorporate arabinotransferases into the arabinogalactan layer.
- inhibits rapidly growing extracellular Mtb
Adverse effects of ethambutol
Optic neuritis and red/green color blindness, which is why we don’t give it to children. They can’t tell us if they can’t see.
Treatment of TB disease in person with HIV
- Need to give more aggressive regiment because they are immunocomprimised
- longer treatment - 9-12 months
- there are adverse reactions with RIF antiretrovirals, which is why we have to switch to rifabutin
Treatment o MAC infection
- much less susceptible than M.tuberculosis to most anti-TBs
- give azithromycin and clarithromycin
- give prophylactic therapy
