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39 Cards in this Set
- Front
- Back
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What are some challenges associated with treating Mycobacterium tuberculosis infections?
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These organisms multiply slowly. They are protected due to their intracellular locations and have a lot of physical barriers protecting them. They have a HUGE propensity to develop resistance to antimicrobial agents (they can become resistant to ANY drug). TB bacteria has both innate resistance and acquired resistance to antibiotics (acquired resistance is always higher than innate resistance though). It is because of this RIDICULOUSLY HIGH level of resistance of the M. TB that we treat the infection with multiple drugs.
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What are some key specifics of TB treatment?
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You ALWAYS treat with a combination of drugs (isoniazid, rifampin, pyrazinamide, and ethambutol). The treatment lasts AT LEAST 6 months.
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What are the 2 main targets of antibiotics against M. TB?
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The mycolic acid layer and the arabinan-galactan layer.
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Why are beta-lactam drugs ineffective against M. TB?
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M. TB produces a LOT of beta-lactamases that cannot be inhibited by beta-lactam inhibitors. The beta-lactams also have a hard time penetrating the mycolic acid layer to get to the peptidoglycan layer.
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How does Isoniazid (INH) work?
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It is a competitive inhibitor of inhA, the enzyme that synthesizes mycolic acid that are required for mycobacterial cell wall synthesis (it inhibits Fatty Acid Synthetase II). It binds tightly to inhA and prevents it from synthesizing the mycolic acid.
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What is REQUIRED for Isoniazid to work?
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It must be activated by catalase/peroxidase (which is encoded for by katG) to work.
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Is INH bacteriostatic or bactericidal?
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Bactericidal to rapidly-dividing organisms
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What are some mechanisms of resistance bacteria have developed against Isoniazid?
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1) Mutating the katG gene resulting in decreased activation of isoniazid. This is the MOST PROMINENT mechanism of resistance.
2) Mutate the inhA gene to result in the overexpression of inhA (so that all the enzyme cannot be bound up by the drug) or mutate the structure of inhA (so that INH cannot bind to it as well). 3) Mutation in the ahpC promoter to lead to its overexpression. ahpC encodes for a catalase that protects the organism from oxidative stress (a job done by katG). This allows the organism to survive with reduced katG activity. |
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What are the pharmacokinetics of Isoniazid?
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It has great bioavailability and is given orally. It is widely distributed throughout the body and gets into the CSF. It is acetylated in the liver to an inactive form (the rate this occurs varies depending on genetics). It is excreted through the kidneys.
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What must be done for someone who is a rapid acetylator in terms of treatment with Isoniazid?
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These individuals have decreased concentrations of Isoniazid in their blood at any one point in time and the drug has a faster half-life in them. You must give people higher levels of the drug to overcome this.
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What are the adverse effects of Isoniazid?
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It can cause peripheral neuritis aka numbness and tingling in the extremities (dose-dependent). It is ALWAYS administered with pyridoxine (vitamin B6) to prevent this.
It can cause hepatotoxicity. This is its major toxicity. The INH metabolites after its acetylation can cause direct hepatotoxicity. This is more common in slow acetylators due to the metabolites staying around longer in them. It is immune-mediated in some cases. It inhibits metabolism of phenytoin and carbamezepine. It has P450 interactions. |
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How does Rifampin work?
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Rifampin inhibits the mycobacterial RNA polymerase
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What type of drug is Rifampin (what organisms does it work against and is it static or cidal)?
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Rifampin is a bactericidal drug. It is a broad spectrum drug that works against gram positive and gram negative bacteria.
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What are the mechanisms of resistance against Rifampin?
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The RNA polymerase is altered preventing rifampin from binding to it. This is the MAJOR way bacteria become resistant to rifampin.
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What are the pharmacokinetics of rifampin?
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It has great bioavailability and can be given orally. It distributes widely throughout the body and penetrates the CSF. It is deacetylated in the liver and has a moderate half-life. It is excreted via the bile.
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What are the adverse effects of Rifampin?
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Rifampin is a relatively safe drug
GI irritation Rash Fever Hepatotoxicity which can lead to jaundice Reddish discoloration of body fluids |
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What overlapping toxicity do you have to be careful about when giving Rifampin and Isoniazid together?
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They both have the potential to cause hepatotoxicity. They have a synergy in their adverse effects (stronger bad effect of hepatotoxicty than the addition of the effect by each drug on its own).
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What is a KEY ADVERSE EFFECT of Rifampin?
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P450 INTERACTION and thus effects on MANY MANY DRUGS (including warfarin)
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How does Pyrazinamide work?
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It inhibits the synthesis of the mycolic acid (fatty acid) necessary for synthesis of the mycobacterial cell wall. It inhibits the enzyme Fatty Acid Synthetase I.
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What must occur for Pyrazinamide to work?
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It MUST BE ACTIVATED by pyrazinamidase to pyrazinoic acid.
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Why can Pyrazinamide and Isoniazid be used together if they both act to inhibit synthesis of mycoid acid?
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Isoniazid inhibits the Fatty Acid Synthetase II enzyme whereas Pyrazinamid inhibits the Fatty Acid Synthetase I enzyme.
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What are the mechanisms of resistance against Pyrazinamide?
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Mutating the pyrazinamidase enzyme resulting in decreased activation of the drug and thus an inability to bind to Fatty Acid Synthetase I.
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Is Pyrazinamide bacteriostatic or bactericidal?
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It is bactericidal at low pHs (such as in an acidic phagosome).
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What are the pharmacokinetics of pyrazinamide?
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It has great bioavailabilty and can be given orally. it is widely distributed throughout the body including the CSF. It has some metabolism (deamindated) and has a long half-life. It is excreted renally.
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What are the adverse effects of Pyrazinamide?
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It is a safe drug.
GI irritation Hepatotoxicity Hyperuricemia (it increases uric acid) |
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How does ethambutol work?
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It inhibits the polymerization of arabinan (via inhibition of arabinosyltransferases) which is necessary for the synthesis of the mycobacterial cell wall. It is a specific drug that is selective for mycobacteria.
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What is the mechanism of resistance against ethambutol?
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You mutate the embB gene that encodes for arabinosyltransferases (the target enzyme of the drug). This prevents the drug from binding to its target.
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Is ethambutol bacteriostatic or bactericidal?
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Bacteriostatic
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What are the pharmacokinetics of ethambutol?
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It has good bioavailabilty and can be given orally. It is widely distributed throughout the body and can get into the CSF. It is metabolized in the liver and has a moderate half-life. It is excreted renally.
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What are the adverse effects of ethambutol?
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Optic neuritis (dose-dependent)- inflammation of the optic nerve leading to decreased visual acuity and color blindness. This is temporary and goes away with stopping treatment.
GI irritation Hyperuricemina |
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What is special about Streptomycin?
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It is an aminoglycoside that was the first effective drug used against TB. It is not used much anymore due to wide-spread resistance against it.
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How does Streptomycin work?
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It inhibits protein synthesis through binding to the 30S ribosomal subunit.
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Is Streptomycin bacteriostatic or bactericidal?
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Bactericidal
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What are the mechanisms of resistance against Streptomycin?
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Alterations in the ribosome:
- Alteration in a protein that binds to the ribosome and helps with translation (more common clinically) -mutation in the ribosomal RNA |
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What are the 2 main adverse effects of Streptomycin?
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Oxotoxicity
Neprotoxicity |
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What are some other drugs that are used to treat TB?
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Ethionamide
Capreomycin Cycloserine Aminoglycosides (kanamycin, amikacin) Fluoroquinolones (levofloxacin, moxifloxacin) |
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What is MDR TB resistant to?
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Isoniazid, rifampin and possibly other drugs
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What is XDR TB resistant to?
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Isoniazid, rifampin, a fluroquinolone and an injectable drug (an aminoglycoside or capreomycin)
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What are some newer, promising drugs that could be used to treat MDR TB or XDR TB?
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1) Bedaquiline- this might be able to be used to MDR TB; it acts on ATP synthase to decrease the ATP in the organism; it makes the other drugs work quicker; it decreases the time to a negative sputum culture; it is a bactercidal drug
2) Linezolid for XDR TB; it inhibits protein synthesis; it is more toxic long-term; it helped patients convert to a negative sputum culture after 6 months of treatment 3) Delamanid for MDR TB; it inhibits mycolic acid synthesis; it acts on ATP synthesis; it helped more patients convert to negative sputum cultures when it was included in 2 months of treatment |
