Lecture #3 - TB & NTM Drugs Flashcards
Isoniazid HCl (INH)
Clinical Use
MOA
- not used as a single drug to treat TB
(ONLY USED AS A SINGLE DRUG FOR LATENT TB only !!! (w/ one drug will develop resistance))
1st line, used in combo
MOA:
- prodrug that is covered to active form by catalase peroxidase (on the TB kata gene)
- targets inhA gene product which affects fatty acid synthesis and disrupts the cell wall mycelia acid
**CIDAL for replicating
static for resting
2 resistance mechanisms of INH
metabolism of INH
Mutations in katG gene - catalase-peroxidase
- INH activation
Mutation of inhA gene - cell wall (mycolic acid) synthesis
- ## Metabolized in LIVER
3 toxicities of INH (isoniazid hcl)
- Heptotoxicity
- Neurotoxicity
- Hypersensitivity rxns (lupus like)
RIFAMPIN
CLinical
MOA & Resistance (which gene)
First line drug for TB – always used in combination (XC for LTBI)
- Note: Cannot be used alone as an antibacterial agent (other than for LTBI or meningitis prophylaxis) b/c of rapid development of resistance
2. Inhibits DNA-dependent RNA polymerase, encoded by the rpoB gene
rpoB mutations can cause rifampin resistance
Bactericidal to all population of organisms
Rifampin
Toxicity (6)
Interactions (4 main, others)
- Hepatotoxicity increased with other hepatotoxic drugs, e.g., INH
2 Red discoloration of body fluids – urine, tears, soft contacts
- Acute renal failure, interstitial nephritis
- Influenza syndrome – more common with intermittent dosing
- Thrombocytopenia***
- Cholestatic jaundice
Interacts with more than 100 drugs since metabolized in liver by CYp350
For example accelerates the clearance and reduces the effective serum concentrations of: methadone, COUMADIN, corticosteroids, ESTROGEN, oral hypoglycemic agents, digoxin, anti-arrhythmic drugs, theophylline, ANTICONVULSANTS, ketoconazole, cyclosporine, ANTIRETROVIRAL drugs
ETHAMBUTOL
CLinical
MOA
(which gene)
- static or cidal
Clinical:
First line TB therapy
A “helper” drug that inhibits resistance to other drugs (weakens cell wall)
MOA:
Inhibits TB arabinosyl transferase encoded by embB gene
Effects cell wall synthesis
Bacteriostatic
ETHAMBUTOL
PK
Toxicity (KNOW THIS)
Pharmacokinetics:
- Reduced dose in renal failure
- Distributed well, except CSF levels low even with inflamed meninges
Toxicity:
1. Optic neuritis – symptoms: blurred vision, central scotomata, red-green color vision loss, dose-related,
Which drug causes optic neuritis & peripheral neuropathy?
BLINDESS & nerve damage
= ETHAMBUTOL
(eyes are fucked)
Pyrazinamide (PZA)
Clinical (test)
- when is it used
MOA
(which gene)
Clinical use
First line TB drug – for the 1st TWO months of therapy
Always used in combination therapy
MOA:
A “prodrug” activated by TB pyrazinamidase, encoded by pncA
Resistance from a variety of pncA gene mutations
Bactericidal
Pyrazinamide (PZA)
PK
Toxicity (3, 1 main)
Pharmacokinetics:
- Accumulates in renal failure
- Distribution is good, including in the CSF in tuberculous meningitis
Toxicity:
1. *Hepatitis, worse in patients with preexisting liver disease
- Skin rash and gastrointestinal intolerance
- Increased serum uric acid levels, but acute gout is uncommon
Streptomycin
Clinical
MOA
PK
Toxicity (2)
Clinical: 2nd line TB drug
MOA:
Inhibits protein synthesis by binding to ribosome
Resistance – mutation of ribosomal binding site
Isolates resistant to streptomycin are NOT cross resistant to amikacin, kanamycin or capreomycin (KEY)
PK:
Excretion renal – reduce dose in renal failure
Enters CSF only in the presence of meningeal inflammation
Toxicity:
1. Ototoxicity
- Nephrotoxicity
(like all AG’s!!!)
Define the difference between primary and secondary resistance to TB drugs
Primary: infected by a source w/ drug resistant TB
Secondary: ineffective therapy
- didn’t take meds
- poor dosing/absorption
What is the rationale for TX with multiple drugs?
Risk of evolution of resistance to two drugs is the product of the risk of the development of resistance to each drug
(add exponents)
define MDR-TB (test)
- specific drugs!
Definition = resistance to both INH and rifampin
More common in HIV infected patients
Nosocomial transmission and high mortality in HIV/AIDS
IF ___ drug is knocked out, treatment is extended to 18 months for TB
RIFAMPIN
Note: Rifampin resistance eliminates short-course (6 month) TB therapy
requires therapy for at least 18-24 months
define XDR- TB
Extensively Drug Resistant TB (XDR-TB)
Definition = resistance to all of the following
- INH and Rifampin (MDR-TB + other resistance)
- Resistance to a fluoroquinolone antibiotic
- Resistance to one of three injectable antibiotics (amikacin, kanamycin, capreomycin)
(test) What is the 6 mon treatment regimen for TB
4-drug regimen (“RIPE” therapy = Rifampin-INH-PZA-Ethambutol)
Initial phase: RIPE
Continuation phase: RI (Note: Emb not needed if pan-sucept.).
If therapy of TB is intermittent and not daily (ex: weekly) what needs to be implemented?
Daily Observation Therapy
ie nurse monitors if you are taking the drug (comes to your house)
How long is tx if mono resistant only to PZA
9 months
T/F: Latent TB will have a positive PPD and positive Quantiferon assay
TRUE
What is the main point about TB and NTM infections?
TREATMENT is different
- NTM is resistant to INH and PZA (no genes for these)
- NTM is not contagious like TB
What drugs are used in both TB and NTM? (4)
Which 2 only for NTM?
Which 1 only for TB
Which 1 works only for TB and M. kansasii?
Both TB & NTM:
- Rifampin
- Ethambutol
- Fluoroquinolone
- Aminoglycoside
NTM only:
- Clarithromycin
- Azithromycin
TB only:
- PZA
TB+ Kansasii:
- INH
What is the tx for Paucibacillary leprosy?
Multibacillay leprosy?
US: rifampin + dapsone for 12 months
US recommendation: rifampin + dapsone + clofazimine daily for 24 months
Which drug causes lupus like symptoms?
Isoniazid
