Term
| Min. # of drugs Tb pts should be on? |
|
Definition
|
|
Term
| Types of therapy that cause/prevent resistance? |
|
Definition
Cause: monotherapy
Prevent: combo therapy |
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Term
| Development of resistance indicates what? |
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Definition
| worse prognosis AND more severe disease |
|
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Term
| How do you handle a failing regimen? |
|
Definition
Put pt on at least 2 drugs they have NEVER had.
DO NOT add a single drug to the failing regimen |
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Term
| 2 categories of therapy you must have in order to effectively treat Tb? |
|
Definition
| 1) Early bactericidal therapy (stop the bugs from growing) AND 2) sterilizing activity (kill off the remaining bugs) |
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Term
| Reasoning behind giving BACTERICIDAL and STERILIZING therapy at the same time during the first 2 months? |
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Definition
| Shortens treatment time (6 instead of 9 mo) AND dec chance of relapse |
|
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Term
| Why does relapse usually occur? |
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Definition
| Tissues were not properly STERILIZED |
|
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Term
Most common drug combo for the first 2 months (bactericidal)?
Why do we use this combo? |
|
Definition
RIPE -- we don't know the sensitivity of the Tb so we use all 4 and hope the drug is sensitive to 2 or 3 of them
Rifampin (RIF)
Isoniazid (INH)
Pyrazinamide (PZA)
Ethambutol (EMB) |
|
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Term
| What do you if during the first 2 months, your pt is on RIPE, and the Tb comes back being INH sensitive? |
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Definition
Stop the EMB (dec chances of SE - vision)! Continue the other 3
You only start them on EMB just in case the Tb is INH resistant. |
|
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Term
| Of RIPE, which 2 are the best sterilizers? |
|
Definition
RIF and PZA
(both are cidal) |
|
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Term
| If you were not able to use PZA during the first 2 months, how long does your pt have to be on Tb drugs? |
|
Definition
9
Pts can only do 6 months of treatment if they have been able to be on PZA the entire first 2 months b/c PZA is a really good STERILIZER, so if you couldn’t sterilize for the first 2 months, must inc the sterilization period (7 months) |
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Term
| Why wouldn't someone be able to be on PZA? |
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Definition
| Liver problems, gout, pregnant |
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Term
| After 2 months of therapy w/ RIP (the bug was INH sensitive, so we dropped the EMB) -- what do you do next? |
|
Definition
Drop the PZA and continue the RIF and INH for 4 more months
Pts will either take it daily, twice weekly, or three times weekly (depending on HIV+/immunocompromised)
If HIV-negative, absence of cavitary disease at presentation, and negative sputum smears at 2 months of therapy then: 1x/week INH-rifapentine |
|
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Term
| What do you do if the pt can't take RIF? |
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Definition
Use PZA throughout the course instead
[I'm not sure how long it would have to be.. my guess is probably the longer (9 mo) but I'm not sure] |
|
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Term
| Most active of all the Tb drugs? |
|
Definition
INH
(one 1 that is both static AND cidal) |
|
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Term
| Quick and dirty summary of Tb treatment |
|
Definition
1) 2 months: RIPE
--drop the EMB if INH sensitive
2) 4 (or 7) months: RIF & INH
***use PZA throughout treatment if can’t use RIF |
|
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Term
| What types of bacteria is RIF effective against? |
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Definition
| mycobacteria, most Gram-positive and many gram negative bacteria |
|
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Term
| Which one is more selective: INH or RIF? |
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Definition
|
|
Term
|
Definition
inhibition of DNA-dependent RNA polymerase → inhibits the synthesis of RNA
***must be in high concentrations to do this! |
|
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Term
| Which Tb drugs have intracellular AND extraceullar activity? |
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Definition
|
|
Term
| Why do you need to give RIF 2x/wk? |
|
Definition
| to avoid a flu-like syndrome of fever, chills and myalgia |
|
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Term
| Which Tb drug has the SE of: red-orange color to the urine, feces, saliva, sweat and tears? |
|
Definition
|
|
Term
|
Definition
rash, fever, nausea and vomiting
Also: induces several P450 isoforms |
|
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Term
| How is RIF self destructive? |
|
Definition
| when administered over longer periods could cause CYP3A auto induction reducing its own systemic exposure |
|
|
Term
Why do you have monitor RIF in ppl with liver problems?
What other Tb drug do you need to monitor for liver function? |
|
Definition
excreted mainly in bile and is subject to enterohepatic recirculation
Other drug: EMB -- 1/2 is excreted in urine and 1/2 in the bile so renal and hepatic function must be monitored |
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Term
|
Definition
|
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Term
| Which Tb drug(s) is a pro drug? |
|
Definition
INH & PZA
INH: activated by catalase-peroxidase (KatG gene)
Deletions or mutations in this gene --> resistance to INH
PZA: metabolized by mycobacteria (nicotinamidase) to pyrazinoic acid (active form)
**only active in acidic places (the edge of necrotic TB where lactic is b/c of inflamm. cells) |
|
|
Term
|
Definition
disrupts cell wall synthesis
by inhibiting the enzymes
--enoyl acyl carrier protein reductase --β-ketoacyl-ACP synthase |
|
|
Term
|
Definition
BOTH!
cidal - growing bacteria
static - resting bacteria |
|
|
Term
| How does renal/hepatic impairment affect the toxicity of INH? |
|
Definition
metabolized partly by acetylation b/c it's a hydrazine
If pt is a slow acetylator, then renal/hepatic impairment → inc toxicity
(***PAS also metabolized by acetylation) |
|
|
Term
|
Definition
hepatitis (inc during pregnancy), lupus like syndrome, convulsions, peripheral neuritis
***Also: inhibits cytochrome P450 |
|
|
Term
True or False
INH and RIF inhibit cytochrome P450 |
|
Definition
FALSE
INH inhibits but RIF INDUCES
Yeah.. I just Parsaed you :) |
|
|
Term
|
Definition
|
|
Term
|
Definition
They can't decide:
either by
1)inhibiting transcription of the mycobacterial fatty acid synthase I (FASI) gene or
2)inhibiting FAS1 itself |
|
|
Term
| If FAS1 isn't allowed to do it's job, what happens? |
|
Definition
interference with
(a) mycolic acid synthesis,
(b) reduction of intracellular pH and (c) disruption of membrane transport by POAH (the protonated form of POA- (pyrazinoic acid)) |
|
|
Term
SE of PZA?
What SE does EMB share with PZA? |
|
Definition
hepatotoxicity, hyperuricemia (can't excrete uric acid) --> acute gout
arthralgias, nausea, vomiting and fever
EMB also has hyperuricemia |
|
|
Term
|
Definition
|
|
Term
|
Definition
| inhibits arabinosyltransferase --> disrupts cell wall synthesis |
|
|
Term
| How does EMB work with the other Tb drugs? |
|
Definition
| disrupts the cell wall thus increasing the penetration of other antiTb drugs |
|
|
Term
|
Definition
retrobulbar neuritis
causing red-green color blindness and loss of visual acuity |
|
|
Term
| How is Rifabutin like RIF? Different? |
|
Definition
Derivative of RIF w/ same mechanism of action
Diff: less potent inducer of cytochrome P450, has SE: polymyalgia, pseudojaundice and anterior uveitis |
|
|
Term
How does Rifapentine compare to RIF and Rifabutin?
(1/2 life? P450?) |
|
Definition
--Longer 1/2 life than other 2
--In between the 2 for inducing cytochrome P450 |
|
|
Term
|
Definition
interferes with cell wall synthesis 2 ways:
1) inhibits alanine racemase
2) inhibits D-ala-D-ala synthetase |
|
|
Term
|
Definition
| serious CNS toxicity, headache, tremors, psychoses and convulsions |
|
|
Term
| ETHIONAMIDE has MOA like which of the 4 big Tb drugs? |
|
Definition
|
|
Term
|
Definition
| gastric irritation, hepatotoxicity, peripheral neuropathies and optic neuritis |
|
|
Term
| 3 aminoglycosides that are also antiTb? |
|
Definition
Streptomycin, Kanamycin, and Amikacin
**Capreomycin is not an AG (it's amixture of four active cyclic peptides) |
|
|
Term
Streptomycin: cidal or static?
Extracellular or intracellular? |
|
Definition
Cidal in vivo (some evidence suggests static in vivo too..)
Extracellular |
|
|
Term
| How does Streptomycin compare to other Tb drugs? |
|
Definition
| less effective and more toxic than other drugs |
|
|
Term
|
Definition
| inhibits initiation of protein synthesis, causes misreading of mRNA → synthesis of faulty proteins and it causes premature termination of protein synthesis by breaking polysomes into nonfunctional monosomes |
|
|
Term
|
Definition
| nephrotoxicity (reversible) and ototoxicity |
|
|
Term
| How do Amikacin/kanamycin compare to streptomycin? |
|
Definition
less toxic
similar MOA
same SEs as streptomycin |
|
|
Term
|
Definition
Levofloxacin, Moxifloxacin, Gatifloxacin
..no CIPRO |
|
|
Term
|
Definition
|
|
Term
|
Definition
| inhibits bacterial DNA gyrase (bacterial eq. of mammallian topoisomerase II which prevents supercoiling) |
|
|
Term
|
Definition
| SE: nausea, headache, dizziness, rash and pseudomembranous colitis (C. difficile) |
|
|
Term
| How is CAPREOMYCIN administered? |
|
Definition
|
|
Term
|
Definition
| inhibits protein synthesis but how is unclear |
|
|
Term
| CAPREOMYCIN: static or cidal? |
|
Definition
|
|
Term
| Why can't you give CAPREOMYCIN w/ streptomycin? |
|
Definition
B/c both are nephrotoxic and ototoxic
**Same rule goes for the other AGs kanamycin and amikacin |
|
|
Term
|
Definition
nephrotoxic and ototoxi
eosinophilia, which is common, hearing loss and tinnitus. |
|
|
Term
| Which 2 drugs are given when the first line agents (RIPE and other 2 Rif's) can't be used? |
|
Definition
| CAPREOMYCIN, PARA-AMINOSALICYLIC ACID (PAS) |
|
|
Term
| MOA of PARA-AMINOSALICYLIC ACID (PAS)? |
|
Definition
| PAS competes with p-aminobenzoic acid in the synthesis of folic acid |
|
|
Term
|
Definition
static
Think about MOA: competes with p-aminobenzoic acid in the synthesis of folic acid.. this prevents growth/reproduction but doesn't kill the bugs that are already there |
|
|
Term
| How does PAS affect INH levels? |
|
Definition
| Both metabolized by acetylation --> PAS competes with INH for the metabolizing enzymes thus increasing the levels of INH |
|
|
Term
|
Definition
| nausea, vomiting, diarrhea, anorexia, epigastric pain, abdominal distress, fever, malaise or joint pain. High drug concentrations in urine can cause crystalluria |
|
|
Term
| Difference b/t cidal and static? |
|
Definition
Static -- the drug simply STOPS growth/reproduction.. it does not harm the bugs that are already there (1000 bugs will stay at 1000 bugs, can not increase but also, will not go down to 0)
Cidal -- Drugs actually KILLS the bugs that currently exist (1000 bugs will eventually go to 0 bugs) |
|
|
Term
|
Definition
INH (both static and cidal)
EMB
FQ
CAPREOMYCIN
PAS |
|
|
Term
|
Definition
INH (both static and cidal)
RIF
PZA
Streptomycin (in vivo) |
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