Antimycobacterials; L3 (12-03-15) Flashcards
Principles of Treatment - Active TB
- *__-drug therapy**
- Enhance rates of __/__ (cult neg. status)
- Reduce emergence of __
- *Focus on increasing __/__**
- __ possible course of therapy
- __ __ therapy (__)
- *Adequate __ of therapy**
- __ cure
- __ relapse
Principles of Treatment - Active TB
- *Multi-drug therapy**
- Enhance rates of response/cure (cult neg. status)
- Reduce emergence of resistance
- *Focus on increasing adherence/Rx completion**
- Shortest possible course of therapy
- Directly observed therapy (DOT)
- *Adequate duration of therapy**
- Increased cure
- Reduced relapse
Isoniazid HCL (INH)
- *Clinical use - not used as a single drug to rx TB (except for __ TB infection)**
- __ line drug for active pulmonary TB
- Used in combo, usually with at least __ other drugs
MOA
- A “__,” must be converted to its active form
- Activated by __ __ (TB __ gene)
- Targets __ gene product -> FA synthesis -> cell wall __ __
- __ for replicating organisms, __ for “resting organisms”
Isoniazid HCL (INH)
- *Clinical use - not used as a single drug to rx TB (except for latent TB infection)**
- 1st line drug for active pulmonary TB
- Used in combo, usually with at least 2 other drugs
MOA
- A “prodrug,” must be converted to its active form
- Activated by catalase peroxidase (TB katG gene)
- Targets inhA gene product -> FA synthesis -> cell wall mycolic acid
- CIDAL for replicating organisms, STATIC for “resting organisms”
Isoniazid HCL (INH)
Resistance mechanisms
- Mutation in __ gene -> __-__ -> INH activation
- Mutation of __ gene -> cell wall (__ __) synthesis
Pharmacokinetics
- Metabolism: INH acetylation in ___ by N-acetyltransferase (acetylation rate is ___ controlled -> slow/rapid acetylators -> can affect __toxicity)
- Distribution: __, including __ (may equal plasma levels with __ inflammation)
Isoniazid HCL (INH)
Resistance mechanisms
- Mutation in katG gene -> catalase-peroxidase -> INH activation
- Mutation of inhA gene -> cell wall (mycolic acid) synthesis
Pharmacokinetics
- Metabolism: INH acetylation in liver by N-acetyltransferase (acetylation rate is genetically controlled -> slow/rapid acetylators -> can affect neurotoxicity)
- Distribution: wide, including CSF (may equal plasma levels with meningeal inflammation)
Isoniazid HCL (INH) (*Card probably not high-yield–no “know this” on slide; included for completion)
Toxicity
- __ - 10-20% of pts have increased __ in 1st month
- __ - more common in slow acetylators–vitamin B6 reduces incidence
- __ rxns - fever, rash, lupus-like
Drug interactions
- INH + __ increases occurrence of hepatitis
- __ toxicity (INH reduces __ clearance)
- Decreases __ levels and __ activity
Isoniazid HCL (INH) (*Card probably not high-yield–no “know this” on slide; included for completion)
Toxicity
- Hepatotoxicity - 10-20% of pts have increased LFTs in 1st month
- Neurotoxicity - more common in slow acetylators–vitamin B6 reduces incidence
- Hypersensitivity rxns - fever, rash, lupus-like
Drug interactions
- INH + rifampin increases occurrence of hepatitis
- Dilantin toxicity (INH reduces dilantin clearance)
- Decreases itraconazole levels and levodopa activity
Rifampin
Clinical use: __ line drug for TB–always used in combo (except for __ TB infection)
Note: cannot be used alone as an antibacterial agent (other than for __ or __ prophylaxis) bc of rapid development of __
MOA: inhibits DNA-dependent __ __, encoded by the __ gene (-> __ mutations can cause resistance); bactericidal to whole population of organisms
Pharmacokinetics: metabolized in the __; penetrates most tissues well (__ increase with inflamed __)
Rifampin
Clinical use: 1st line drug for TB–always used in combo (except for latent TB infection)
Note: cannot be used alone as an antibacterial agent (other than for LTBI or meningitis prophylaxis) bc of rapid development of resistance
MOA: inhibits DNA-dependent RNA polymerase, encoded by the rpoB gene (-> rpoB mutations can cause resistance); bactericidal to whole population of organisms
Pharmacokinetics: metabolized in the liver; penetrates most tissues well (CSF increase with inflamed meninges)
Rifampin
Toxicity
- __ increased with other __ drugs, e.g., INH
- __ discoloration of body fluids - urine, tears, etc.
- (3 other uncommon toxicities mentioned on slide)
Drug interactions
-__ hepatic microsomal enzymes -> interacts with > 100 drugs
Rifampin
Toxicity
- Hepatotoxicity increased with other hepatotoxic drugs, e.g., INH
- Red discoloration of body fluids - urine, tears, etc.
- (3 other uncommon toxicities mentioned on slide)
Drug interactions
-Induces hepatic microsomal enzymes -> interacts with > 100 drugs
Ethambutol
Clinical use: __ line TB therapy; a helper drug that inhibits __ to other drugs
MOA: inhibits TB __ __, encoded by __ gene; affects cell __ synthesis; bacterio__
Pharmacokinetics: reduced dose in __ failure; distributed well, except __ levels LOW even with inflamed __
Toxicity:
1) **__ __ - symptoms: __ vision, central scotomata, __-__ __ vision loss, dose-related, less than 1% incidence
Ethambutol
Clinical use: 1st line TB therapy; a helper drug that inhibits resistance to other drugs
MOA: inhibits TB arabinosyl transferase, encoded by embB gene; affects cell wall synthesis; bacteriostatic
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, less than 1% incidence
Pyrazinamide (PZA)
Clinical use: __ line TB drug - for the 1st __ months of therapy; always used in combo therapy
MOA and resistance: a __ activated by TB __, encoded by __ (-> mutations lead to resistance); bacteri___
Pharmacodynamics: accumulates in __ failure; distribution is good, including in the __ in tuberculous __
Toxicity: hepatitis, skin rash and GI intolerance, increased serum __ __ levels (acute __ uncommon tho)
Pyrazinamide (PZA)
Clinical use: 1st line TB drug - for the 1st two months of therapy; always used in combo therapy
MOA and resistance: a prodrug activated by TB pyrazinamidase, encoded by pncA (-> mutations lead to resistance); bactericidal
Pharmacodynamics: accumulates in renal failure; distribution is good, including in the CSF in tuberculous meningitis
Toxicity: hepatitis, skin rash and GI intolerance, increased serum uric acid levels (acute gout uncommon tho)
TB resistance and multi-drug therapy
- *Primary resistance (acquired __ __)**
- Infection by a __ __ with drug-resistant TB
- *Secondary resistance (developed __ therapy)**
- From ineffective __ (poor __ __ or __)
Risk of evolution of resistance to 2 drugs is the __ of the risk of the development of resistance to each drug (i.e., __ the 10^x exponents together)
TB resistance and multi-drug therapy
- *Primary resistance (acquired at infection)**
- Infection by a source case with drug-resistant TB
- *Secondary resistance (developed during therapy)**
- From ineffective therapy (poor tx design or adherence)
Risk of evolution of resistance to 2 drugs is the product of the risk of the development of resistance to each drug (i.e., add the 10^x exponents together)
TB Resistance - MDR and XDR TB
Multi-drug resistant TB (MDR-TB)
- Definition = resistance to both __ and __
- More common in __-infected pts
Note: __ resistance eliminates short-course (__ month) TB therapy) -> requires therapy for at least __-__ months
Extremely Drug Resistant TB (XDR-TB)
- Definition: resistance to ALL of the following:
1) __ and __
2) __ resistance
3) Resistance to 1 of 3 injectable antibiotics (__, __, __)
TB Resistance - MDR and XDR TB
Multi-drug resistant TB (MDR-TB)
- Definition = resistance to both INH and rifampin
- More common in HIV-infected pts
Note: rifampin resistance eliminates short-course (6 month) TB therapy) -> requires therapy for at least 18-24 months
Extremely Drug Resistant TB (XDR-TB)
- Definition: resistance to ALL of the following:
1) INH and rifampin
2) Fluoroquinolone resistance
3) Resistance to 1 of 3 injectable antibiotics (amikacin, kanamycin, capreomycin)
6-Month TB Tx Regimens
- *Effective therapy of TB - __% cure rate, less than __% relapse rate**
- 4 drug regimen (“__” therapy = __, __, __, __)
- Initial phase: __
- Continuation phase: __ (note: Emb not needed if pan-susceptible)
- Note: intermittent (__-__ times per week) therapy ONLY WITH DOT
- 6 month therapy can be used with a high success rate, if: __ is high, sputum cultures convert by __ months, and there is no major __ lung disease
6-Month TB Tx Regimens
- *Effective therapy of TB - 95% cure rate, less than 5% relapse rate**
- 4 drug regimen (“RIPE” therapy = rifampin, INH, PZA, ethambutol)
- Initial phase: RIPE
- Continuation phase: RI (note: Emb not needed if pan-susceptible)
- Note: intermittent (2-3 times per week) therapy ONLY WITH DOT
- 6 month therapy can be used with a high success rate, if: adherence is high, sputum cultures convert by 2 months, and there is no major cavitary lung disease
Treatment of “mono-resistant” TB
- __ monoresistant -> Rm, Emb, PZA, 6 months -> good outcomes
- __ or __ monoresistant (uncommon) -> does not reduce efficacy or require >6 mo tx
- __ monoresistant (uncommon) -> extension of therapy to 9 mo
-__ monoresistant -> INH, Emb, PZA -> REQUIRES >12-18 month therapy!!
Note: loss of __ from the regimen means loss of the option for short-course (6 month) TB therapy
Treatment of “mono-resistant” TB
- INH monoresistant -> Rm, Emb, PZA, 6 months -> good outcomes
- Ethambutol or streptomycin monoresistant (uncommon) -> does not reduce efficacy or require >6 mo tx
- PZA monoresistant (uncommon) -> extension of therapy to 9 mo
-Rifampin monoresistant -> INH, Emb, PZA -> REQUIRES >12-18 month therapy!!
Note: loss of rifampin from the regimen means loss of the option for short-course (6 month) TB therapy
Tx of NTM infections vs. TB regimens
-Some antibiotics are active against both TB and NTM, whereas others are uniquely active against one or the other type of mycobacteria
- TB only: __, __
- TB and NTM: __, __, __, __
- NTM only: __, __
Tx of NTM infections vs. TB regimens
-Some antibiotics are active against both TB and NTM, whereas others are uniquely active against one or the other type of mycobacteria
- TB only: PZA, INH
- TB and NTM: rifampin, ethambutol, fluoroquinolone, aminoglycoside
- NTM only: clarithromycin, azithromycin
Treatment of leprosy vs TB regimens
-__ __ treatment __ TB treatment
Treatment of leprosy vs TB regimens
-Very different treatment from TB treatment
