Exam 4 - Tuberculosis Flashcards
what bug causes tuberculosis?
mycobacterium tuberculosis
gram stain of mycobacterium tuberculosis?
Aerobic
non-spore forming
bacillus
what are factors associated with MDR-TB?
inadequate therapy (monotherapy or suboptimal dose) Cavitary lesions
what drug combo is most commonly used for active TB treatment?
RIPPE
Rifampin, Isoniazid, Pyrazindamide, Pyridoxine (B6), Ethambutol
Mycobacterium tuberculosis:
_____ rich cell wall that contains _______ and is _______ to many durgs
Lipid rich
contains mycolic acid
impermeable to many drugs
Transmission of Tb:
Only _____ Tb infections can be transmitted
active
Transmission of Tb:
spread by __________
aerosol droplets (speaking, coughing, spitting)
what are the extrapulmonary tuberculosis things that can happen?
genitourethral tuberculosis
TB w/ arthritis or osteomyelitis
TB menigitis
Issues with HIV and diagnosis of TB?
HIV patients have weak immune systems —- they wont have a positive response to skin testing as easily (high false negative rate)
Clinical presentation for TB in healthy patients?
Fever/chills NIGHT SWEATS anorexia wt loss cough hemoptysis/SOB malaise
Clinical presentation of TB in HIV patients?
if early HIV — kinda similar… extrapulmonary at higher risk
if late HIV — v high extrapulmonary disease risk
2 main ways to screen for TB?
PPD (purified protein derivative)
IGRAs (interferon gamma release assays)
when to do IGRA over PPD for diagnosis?
when pts have rcvd BCG vaccinated
T or F: only need to do drug susceptibility for TB when i HIV pts?
false — do it for every isolate!!
Someone is deemed noninfectious when receiving effective therapy, improving clinically, and ??
pt has negative sputum smear results for 3 CONSECUTIVE days (each sputum collected on a different day)
what are the 2 phases for TB treatment?
intensive phase then continuation phase
If pts have HIV and you want to treat TB….
- If pts have CD4 < 50 cells/uL start ART within ______ of TB therapy
- If pts have CD4 >/= 50 cells/uL start ART within ______ of TB therapy
< 50: within 2 weeks
> 50: delay ART until 8 - 12 weeks
Rifampin is a hella _______ of CYP
inducer
_________ is the most active FQ against M. tuberculosis
Moxifloxacin
For MDR-TB:
Treat any patient with ______ resistant TB (or if _____ resistance is absent or unknown with a MDR-TB regimen
rifampin resistant; INH resistance unknown
For MDR-TB:
Must include what 3 drugs for sure for treatment?
A FQ (Levo or moxi) \+ Bedaquiline \+ Linezolid
Treatment options for latent TB infection?
Rifampin QD x 4 mos
INH + Rifapentine once weekly x 12 weeks
INH daily x 6 - 9 mos
INH: how metabolized?
by liver — N-acetyltransferase
INH: into CSF?
yas – super well
INH: good or bad oral bioavail?
good
ADEs of INH?
Hepatitis
Neurotoxic = PERIPHERAL NEUROPATHY — give Vit. B6
Dose adjustments for INH?
when severe hepatic insufficiency or renal failure
why supplement B6 with INH therapy?
INH increases pyridoxine excretion — need it to prevent peripheral neuropathy
INH: inducer or inhibitor of P450?
inhibitor
ADEs of rifampin?
Hepatoxicity discolored urine (sweat and tears)/(orange color) -- can permanently stain contact lenses
ADEs of Pyrazinamide?
Hepatoxicity
Hyperuricemia
Joint pain - arthralgias (MCMP notes)
ADEs of Ethambutol?
Peripheral neuropathy Optic neuritis (can be irreversible if not discontinued)
ADEs of streptomycin?
otoxicity
nephrotoxicty
(it is a aminoglycoside!!)
Do you renal dose adjust for Pyrazinamide or Ethambutol?
Ethambutol
ADE with PAS (P-aminosalicylic acid)
GI!! -take with meals
ADEs of Cycloserine?
“PSYCHO-serine”
depression/personality changes/psychosis/seizures
INH has to be activated by the ______ protein
KatG (comes M.tb)
INH forms adducts with _______ and ______
NAD+ and NADP+
what enzymes are inhibited by the INH/NAD+/NADP+?
InhA and KasA (inhibits mycolic acid synthesis)
DHFR (dihydrofolate reductase)
Activated INH inhibits _______ which is a component of ________ synthase
inhibits: InhA FAS II (fatty acid synthase)
(overall affects arabino-galactan – part of mycobacterium
Overall INH leads to a ________ (why it is good at killing Tb)
leads to defective cell wall
INH resistance happens via what?
by over expression of InhA
and somehow activation of INH by KatG is stopped (Tb probs stops making Katg)
INH is metabolized how?
acetylated by N-acetyltransferase
INH Toxicity Mechanism:
Acetylisoniazed can become _________ (which I think is a toxic metabolite…)
acetylhydrazine
INH Toxicity Mechanism:
_______ converts to hepatotoxic metabolites
CYP2E1
INH Toxicity Mechanism:
_____ can acetylate acetylhydrazine to nontoxic diacetyhdrazine
NAT2
what does AFB stand for
acid fast bacteria
what does it mean to be AFB?
the bug stains SUPER well and cannot be decolorized
Pathology of Tb:
- bacteria phagocytosed by alveolar macrophages in the lung/ cause proinflammatory response
- Recruited cells (such as _______ cells) will form a _______
recruited cells = mononuclear cells
form a granuloma (tubercle)
Pathology of Tb:
- Granuloma forms a _________ with fewer ________ in later stages
- When immune status change containment fails
- The granuloma ________ and spills viable/infectious bacilli into airways
forms a fibrous sheath; fewer penetrating blood vessels in later stages
granuloma caseates/decays/ruptures
Always a 10% lifetime risk of developing active infection when pt has latent Tb
but what things increase risk of activation of Tb?
Diabetes
HIV
Old age
malnutrition
INH Toxicity Mechanism:
(fast or slow) acetylators will lead to toxic metabolites
(fast or slow) acetylators will remove acetylhydrazine
slow = toxic fast = removes the toxic metab
INH Toxicity Mechanism:
Induction of CYP________ leads to toxic metabolites
CYP2E1
INH Toxicity Mechanism:
_______ induces CYP2E1 and potentiates INH hepatotoxicity
rifampin
MCMP reason why we need to supplement B6 with INH therapy?
INH inhibits metabolism of pyridoxine to pyridoxal phosphate….
How is Pyrazinamid activated?
by pncA which is a nicotinamidase from M.Tb
gets converted to pyrazinoic acid
Pyrazinamide (PZA) is structurally similar to ________
nictinamide
Pyrazinamide (PZA):
facts about it being active in relation to pH?
NOT active at neutral pH/
WILL BE active if pH < 5.5
3 ideas of how Pyrazindamide works?
- inhibition of trans-translation
- inhibition of aspartate decarboxylase PanD
- Acidification of cytoplasm followed by disruption of energy metabolism
Pyrazinamide MOA Guess: Trans-Translation:
It gets converted to pyrazinoic acid and will bind and inhibit ______________
ribosomal protein S1 (RpsA) = proteins won’t fold correctly
PZA = ? POA = ?
PZA = pyrazinamide POA = Pyrazinoic Acid
Pyrazinamide MOA Guess: inhibit PanD
panD normally converts ________ to ______
L-aspartate to alanine
Pyrazinamide MOA Guess: inhibit PanD
(PZA or POA) binds to PanD
POA (the activated form) does bind
wont bind to mutant panD tho = resistance
Pyrazinamide MOA Guess: inhibit PanD
overall will reduce the accumulation of ________ after the panD step
which will increase levels of _______
coA precursors;
free fatty acids
MOA of Ethambutol: Inhibits \_\_\_\_\_\_\_\_\_\_ (which is involved in \_\_\_\_\_\_\_\_\_)
this causes a build up of ________
mycobacterial arabinosyl transferases;
polymerization of arabinogalactan;
build up of arabinan
Ethambutol:
is synergistic with _______
rifampin (increases penetration into cell)
Resistance to Ethambutol happens how?
over expression of or mutations of arabinosyl transferase
INH:
active against latent, growing or both forms of Tb?
JUST growing forms
Rifampin:
active against latent, growing or both forms of Tb?
both!!
Rifampin is most effective when the cell is _______
dividing
MOA of Rifampin:
Binds to ________ deep within the ________
to RNA pol
within DNA/RNA channel
Bacteriocidal or Bacteriostatic?
Rifampin?
Ethambutol?
Rifampin:cidal
Ethambutol: static
Rifapentine:
is a derivative of rifampin
it is more _______ and has a ______ half life
lipophilic
longer 1/2 life
Which aminoglycoside can be used for Tb?
Streptomycin (idk if others cant but they talk about streptomycin…)
Streptomycin and Tb:
most active against ______ forms
extracellular
Streptomycin and Tb:
used mainly when severe tuberculosis (ex: _______ or _______0
meningitis or disseminated
Bedaquiline:
Given PO or IV?
cidal or static?
active against latent, growing or both forms of Tb?
PO
cidal
both!
Bedaquiline MOA?
inhibits ATP synthase
what are some 2nd line agents fro Tb?
FQs Ethionamide para-aminosalicylic acid Cycloserine Carpreomycin
when to consider 2nd line agents for Tb?
if resistant to 1st line…
failure of clinical response to first line agents
intolerance of first line
have expert guidance available to deal with toxic side effects
why are the 2nd line agents for Tb used as 2nd line?
less well tolerated/greater incidence of side effects…..(SHOCKING)
