TB agents

what are first line agents for TB

isoniazid, rifamycins, pyrazinamide, ethambutol

how does isoniazid work

prodrug activated by KatG → no mycolic acid

how do rifamycins work

bind beta subunit of DNA-dependent RNA polymerase → no transcription

how does pyrazinamide work

prodrug converted to pyrazonic acid — works only in acid

how does ethambutol work

blocks arabinosyl transferase

what is isoniazid first line in

active and latent TB

what is isoniazid’s role in active TB therapy

component that is the rapid early killer — remember active TB requires multi-drug therapy

what acetylates isoniazid

NAT2

what happens to slow acetylators in isoniazid therapy

more neuropathy

how should isoniazid be taken

on an empty stomach

what can cause resistance to isoniazid

KatG mutation

boxed warning for isoniazid

severe, sometime fatal hepatitis — may occur after many months, risk rises with age and daily alcohol consumption

check AST/ALT at baseline and periodically from age 35

what is a common side effect of isoniazid and what can be done to help

peripheral neuropathy — give pyridoxine (vit B6)

what is a sign of isoniazid overdose

seizures that phenytoin and barbiturates do not stop

what is the antidote for isoniazid overdose

IV pyridoxine

what enzymes does isoniazid inhibit

2C19 and 3A

what enzyme does isoniazid induce

CYP2E1 — can cause acetaminophen liver toxicity

which rifamycins are first line in active TB

rifampin, rifapentine

what rifamycins are first line in latent TB

rifapentine, rifampin

which rifamycin is the best sterilizing drug

rifampin — kills persisting bacilli

which rifamycin is long-acting

rifapentine — allows for weekly dosing

which rifamycin has fewer drug interactions

rifabutin

how should rifampin be taken

on an empty stomach

which rifamycin requires dose adjustment in renal impairment

rifabutin — reduce dose at CrCl <30

what can cause resistance to rifamycins

rpoB mutation

what drug class causes orange-red urine, sweat, tears, and saliva

rifamycins

what is rifampin contraindicated in

HIV drugs

what are serious side effects of rifamycins

hepatotoxicity, flu-like hypersensitivity syndrome

which rifamycin can cause neutropenia and uveitis

rifabutin

which rifamycin is a potent inducer of CYP3A

rifampin — lowers warfarin (and INR), hormonal contraceptives

which rifamycin is a weak inducer and CYP3A substrate

rifabutin

what is pyrazinamide first line in

active TB

what is pyrazinamide’s role in active TB therapy

shortens therapy to 6 months

what enzyme activates the prodrug pyrazinamide

pyrazinamidase — active only at acidic pH

what disease state is pyrazinamide contraindicated in

acute gout — because it causes hyperuricemia

what is the most serious effect of pyrazinamide

hepatotoxicity

what is ethambutol first line in

active TB — mycobacteria only

what is the role of ethambutol in active TB therapy

protects companion drugs from resistance

is ethambutol static or cidal

static

what is ethambutol contraindicated in

optic neuritis and patients who cannot report vision changes (children, unconscious) — eye exam at baseline and during therapy

what is optic neuritis

loss of visual acuity and red-green color discrimination — caused by ethambutol

what drugs can lower the absorption of ethambutol

aluminum antacids

how does bedaquiline work

blocks ATP synthase

which drug for resistant TB is a prodrug

pretomanid

what are first line agents for multi-drug resistant/rifampin-resistant TB

bedaquiline and pretomanid

what is the therapy regimen for drug resistant TB

BPaLM — bedaquiline, pretomanid, linezolid, moxifloxacin

why should bedaquiline be taken with food

doubles absorption

why does bedaquiline work for months after treatment ends

has a LONG terminal half life

what can bedaquiline have cross resistance with

clofazimine

boxed warning for bedaquiline

QT prolongation

what are side effects of drug resistant TB regimens

hepatotoxicity, peripheral and optic neuropathy, myelosuppression