TB Drugs Flashcards
Give some reasons that mycobacteria are intrinsically resistant to many antibiotics
- slow growing organisms, not hit by antibiotics that act only against growing cells
- Mycolic acid residues in wall renders in impermeable to many agents
- intracellular pathogens- inaccessible to drugs that do not penetrate macrophages
- rapidly develop resistance mutations
Isoniazid is a ___ that is converted to an isonicotinoyl radical by ____, a mycobacterial heme-containing catalase-peroxidase enzyme.
prodrug
KatG
Isonicotinoyl radicals formed by KatG react with ___ and ___ to form adducts.
NAD and NADP
Describe the action of the isonicotinoyl-NAD adduct
inhibits enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA), decreasing the synthesis of mycolic acid and leading to cell death
Describe the action of the isonicotinoyl-NADP adduct
inhibits DHFR to reduce nucleic acid synthesis
Genetic variations in acetylation rate are relevant in the parmacokinetics of _____
isoniazid
List two major adverse effects of isoniazid and how to manage them
Elevated LFTs/ hepatitis- monitor LFTs and avoid alcohol and acetaminophen
Neuropathy- administer vitamin B6 to prevent
Rifampin is a broad spectrum antibiotic that can be used to treat:
TB, gram positive and gram negative bacteria and micobacteria
DOC for leprosy, DOC for prophylaxis of H. influenzae meningitis and meningococcal disease
Rifampin is bactericidal- it binds to the Beta subunit of ___________ and inhibits _____ synthesis of ________
RNA polymerase, proteins
Rifampin resistance arises from point mutations in rpoB, the gene encoding for_________
Beta subunit of RNA polymerase
List side effects of rifampin
GI: DVD, cramps, hepatitis
CYP induction- drug interactions
flu like symptoms
Red-orange discoloration of bodily fluids
Precautions for rifampin use include hepatic disease and if CrCL is less than 10 mL/min, dose should be reduced by _____
50%
Ethambutol is a first line TB agent with a complex mechanism of action:
blocks arabinosyl transferase III involved in cell wall biosynthesis; appears to inhibit RNA synthesis, resulting in impaired protein synthesis; may interfere with mycolic acid biosynthesis
Ethambutol is only effective against bacilli that are actively dividing, so it is _______
bacteriostatic
Metabolism of ethambutol is via _________
sequential oxidation of alcohols resulting in dicarboxylic acid metabolite
The most common adverse effect of ethambutol is _________
optic neuritis resulting in decreased visual acuity and red-green color blindness
List precautions for ethambutol
optic neuritis
monitor visual function
adjust dosage for renal impairment
gout- can interfere with uric acid excretion
Pyrazinamide requires metabolic activation (hydrolysis) to ________ by tuberculin _______ enzyme
pyrazinoic acid
pyrazinamidase enzyme
Describe the proposed mechanisms of action of pyrazinamide
1) inhibition of eukaryotic-like fatty acid synthetase I of M. tuberculosis
2) reduction of intracellular pH
3) disruption of membrane transport
Pyrazinamide is ______ at low concentrations and _______ at high concentrations
bacteriostatic at low
bactericidal at high
List adverse reactions to pyrazinamide
Hetaptotoxicity
Hyperuricemia
Rash, photosensitivity
Arthralgia
List precautions for pyrazinamide
hepatic disease, gout, interferes with urine ketone determination
List some second line TB therapeutic agents
Ethionamide
Aminoglycoside antibiotics- bind to 30S, inhibit protein synthesis
Fluoroquinolone antibiotics- inhibit topoisomerase
List some aminoglycoside antibiotics
amikacin, gentamicin, kanamycin, neomycin, tobramycin, streptomycin; all are amino sugars
Describe the spectrum of activity of aminoglycoside antibiotics
Mostly gram negative, aerobic bacilli including E coli, Klebsiella, Enterobacter, Proteus, Pseudomonas
Describe the mechanism of action of aminoglycosides
Bactericidal- inhibit protein synthesis by binding 30S
Describe the mechanism of resistance to aminoglycosides
Resistance via inactivating enzymes, increased expression of efflux pumps, mutations in 30S subunit components 16S mRNA and ribosomal protein S12
True or false: aminoglycosides are great for at-home therapy because they are well absorbed in PO form
FALSE- must be given parenterally, IV at clinic
The major elimination route of aminoglycosides is __________; excretion is directly proportional to ______________ and adjustments in dosing should be made accordingly
glomerular filtration; creatinine clearance
List some toxicities of aminoglycosides
Ototoxicity Nephrotoxicity Curare-like neuromuscular blockade Allergic skin reaction/ contact dermatitis Pregnancy Risk D
__________ is a fluoroquinolone antibacterial agent for second line TB therapy in relapse, treatment failure, or resistance to first line agents
Moxifloxacin
Describe the mechanism of action of moxifloxacin
Interferes with bacterial DNA function by stabilizing topoisomerase II- and topoisomerase IV-DNA cleavage complexes, inhibiting DNA duplication, transcription, repair, and recombination
How does moxifloxacin resistance arise?
Mutations in topoisomerase and by multi-drug efflux pumps (P glycoprotein)
List side effects of moxifloxacin
NVD, abdominal discomfort
Joint swelling, tendinitis, tendon rupture
QT prolongation, mild
Worsening of myasthenia gravis due to neuromuscular blockade
List precautions for moxifloxacin
Myasthenia gravis
Long QT syndrome or on IA or III anti-arrythmai drugs
Moxifloxacin shortens the time to __________________
sputum culture conversion
A newly approved TB drug, _________, works by binding to mycobacterial ________________ to inhibit production of ____
bedaquiline
ATP synthase
ATP
List adverse reactions to bedaquiline
GI
MSK
Headache
QT prolongation- get baseline and serial EKGs
Why is it important to use multidrug regimens to treat TB?
decreased likelihood of resistance
with monotherapy: Isoniazid and rifampin both have a rate of ~ 1 resistance mutation in every 10^6 bacilli. Since lesions often contain more than 10^8 bacilli, TX of active tuberculosis with one drug results in the rapid emergence of resistance
Drugs used for TB are often synergistic and can shorten:
treatment period
infectious period
spread of disease
In biphasic regimens, at what point does the switch from initial phase to continuation phase occur?
culture conversion (disappearance of bacilli from sputum)
List some populations that should be prioritized for directly observed therapy
Pulmonary tuberculosis with positive sputum smears Treatment failure, relapse Drug resistance HIV infection Prior treatment for either active or latent tuberculosis infection Current or prior substance abuse Psychiatric illnesses, memory impairment Previous nonadherence to therapy Children and adolescents
Describe the standard TB regimen for active disease
- Daily-to-thrice weekly INH + RIF + PZA + EMB for 8 weeks
- If organisms are susceptible (areas of < 4% isoniazid resistance), can DC EMB
- If isoniazid resistance is > 4%, add EMB or streptomycin
Describe the continuation phase for active TB treatment
daily to once weekly INH + RIF for 18 weeks
Describe prophylactic therapy for latent TB
Isoniazid monotherapy for 6-9 months
Why are once weekly INH + RIF continuation phase regimens contraindicated in people who are HIV+?
unacceptably high rate of relapse, frequently with organisms with acquired resistance to rifamycins
What drug is used for treatment of leprosy?
Dapsone
What is the mechanism of action of dapsone?
Inhibition of dihydropteroate synthase, decreased folic acid, decreased DNA synthesis
What is a major adverse effect of dapsone treatment?
Hemolysis, anemia, leukopenia
