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Respiratory II Exam 2 > TB Pharm > Flashcards

TB Pharm Flashcards

1
Q

TB First-Line agents

A 
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
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2
Q

TB Second-line (and 3rd line) agents

A 
Ethionamide
Capreomycin
Cycloserine
Aminosalicylic Acid (PAS)
Kanamycin & Amikacin
Fluoroquinolones
Linezolid
Rifabutin
Rifapentine
Bedaquiline
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3
Q

Tuberculosis (TB) characteristics

A

Cell envelope – three macromolecules (peptidoglycan, arabinogalactan, mycolic acids) linked to lipoarabinomannan (lipopolysaccharide)
Acid-fast bacillus (AFB)
Slow growth rate

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4
Q

Natural History of Infection

A

Transmission: airborne route
- Droplet nuclei expelled into air when a patient with pulmonary TB coughs, sneezes, or spits

Inhalation of droplets leads to 4 possible outcomes:

  • Immediate clearance of organism
  • Primary disease
  • Latent infection
  • Reactivation disease
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5
Q

Isoniazid (INH) MOA, Resistance

A

MOA: inhibits synthesis of mycolic acids
Prodrug, activated by KatG
Active form binds AcpM and KasA –> inhibits mycolic acid synthesis

Resistance:
Mutation or deletion of katG gene
Overexpression of inhA and ahpC
Mutation in kasA

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6
Q

Isoniazid (INH) ADRs

A 
Hepatotoxicity
- Minor elevations in LFTs (10-20%)
- Clinical hepatitis (1%)
Peripheral neuropathy
CNS toxicity (memory loss, psychosis, seizures)
Fever, skin rashes, drug-induced SLE
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7
Q

Rifampin (RIF) MOA

A

MOA: inhibits RNA synthesis
Binds B-subunit of DNA-dependent RNA polymerase (rpoB)

Resistance:
Reduced binding affinity to RNA polymerase –> point mutations within rpoB gene

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8
Q

Rifampin (RIF) ADRs/ DDIs

A

ADRs:

  • Nausea/vomiting (1.5%)
  • Rash (0.8%)
  • Fever (0.5%)
  • Harmless red/orange color to secretions
  • Hepatotoxicity
  • Flu-like syndrome (20%) in those treated < 2x/week

DDIs:
*** Induces CYPs 1A2, 2C9, 2C19, and 3A4

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9
Q

Pyrazinamide (PZA) MOA, resistance, ADRs

A

MOA: disrupts mycobacterial cell membrane synthesis and transport functions

  • Macrophage uptake, conversion to pyrazinoic acid (POA-)
  • Efflux pump to extracellular milieu
  • POA- protonated to POAH, reenters bacillus

Resistance:
Impaired biotransformation, mutation in pncA

ADRs:
Hepatotoxicity (1-5%)- perhaps the most hepatotoxic
GI upset
Hyperuricemia

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10
Q

Ethambutol (EMB) MOA, Resistance, ADRs

A

MOA: disrupts synthesis of arabinoglycan
- Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)

Resistance:

  • Overexpression of emb gene products
  • Mutation in embB gene

ADRs:
*** Retrobulbar neuritis (loss of visual acuity, red-green color blindness)
Rash
Drug fever

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11
Q

Streptomycin MOA, Resistance, ADRs

A

MOA: irreversible inhibitor of protein synthesis
- Binds S12 ribosomal protein of 30S subunit

Resistance:
- Mutations in rpsL or rrs gene which alter binding site

ADRs:

  • Ototoxicity (vertigo and hearing loss)
  • Nephrotoxicity
  • Relatively contraindicated in pregnancy (newborn deafness)
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12
Q

Antimycobacterial Drugs ADRs

A 
ADRs with 1st-line agents are common
Hepatotoxicity
- May be caused by INH, RIF, or PZA
- Asymptomatic increase in AST (20%)
- Hepatitis (AST ≥ 3 ULN + symptoms or ≥ 5 ULN +/- symptoms) – discontinue

Ocular Toxicity
- May be due to EMB

Rash

  • All agents may cause rash
  • Minor pruritic rashes – antihistamines + continue drug therapy
  • Petechial rash + thrombocytopenia – discontinue rifampin
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13
Q

Clinical Presentation of TB

A 
Signs/Symptoms:
Weight loss
Fatigue
Productive cough
Fever
Night sweats
Frank hemoptysis

Chest Radiograph:
Patchy or nodular infiltrates
Cavitation

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14
Q

TB treatment Outcomes:

A 
Rapid identification of infection
Initiation of appropriate drug regimen
Resolution of signs/symptoms
Achievement of non-infectious state
Appropriate drug adherence
Rapid cure (at least 6 months of treatment)
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15
Q

TB treatment approach

A

Monotherapy may only be used in latent infection
Active disease requires a minimum of two drugs (generally 3-4)
Shortest duration of treatment = 6 months (up to 2-3 years in MDR-TB)
Directly observed therapy = standard practice

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16
Q

Directly Observed Therapy (DOT)

A

Compared to self-administered therapy (SAT):

  • Improved treatment success (# cured + # completing treatment)
  • Increased sputum smear conversion

Recommended for those:

  • With drug-resistant infections
  • Receiving intermittent regimens
  • With HIV
  • And children
17
Q

Combination Drug Therapy

A

Drug resistant mutants – 1 bacillus in 10^6
Asymptomatic patients – bacillary load of 10^3
Cavitary pulmonary TB – bacillary load > 10^8
Resistance readily selected out if single drug used

Combination therapy, drug resistance – 1 bacillus in 10^12
Rates of resistance additive functions of individual rates
Example: only 1 in 10^13 organisms would be naturally resistant to both isoniazid (1 in 10^6) and rifampin (1 in 10^7)

2+ active agents should always be used for active TB to prevent resistance

Most active anti-TB drugs = INH and RIF
Combination (x9 months) cures 95-98% of susceptible TB cases
Regimens without a rifamycin are less effective

Adding PZA for first 2 months allows for 6 months total duration

Once susceptibility known, discontinue ethambutol from the 4 drug regimen

18
Q

Latent Tuberculosis Infection (LTBI)

A

Lifetime risk of active disease reduced from 10% to 1% with treatment

Treatment options:

  • Isoniazid (INH) daily or twice weekly x 9 months
  • INH + rifapentine weekly x 12 weeks by DOT
    • –Must be ≥ 12 years; includes HIV patients not on ART
  • Rifampin daily x4 months
    • –Patients intolerant to INH or with INH-resistant strains
19
Q

Active Disease treatment

A

Drug susceptibility on initial isolate for all patients with active TB

Standard of therapy includes:
Initial phase – 2 months
Continuation phase – 4 or 7 months

Patient monitoring:
Adverse reactions
Adherence
Response to treatment

20
Q

Initial Phase:

of active disease treatment

A

Until susceptibility available – INH + RIF + EMB + PZA
When susceptibility to INH, RIF, or PZA documented – may discontinue EMB
Those who cannot take PZA should receive INH, RIF, and EMB

21
Q

Continuation phase of active disease treatment

A

Two factors which increase risk of treatment failure –
- Cavitary disease at presentation
- Positive sputum culture at 2 months
0-1 risk factor: INH + RIF x 4 months (6 months total)
2 risk factors: continuation phase x 7 months (9 months total)

22
Q

Drug-Resistant Active TB

A

Drug-Resistant TB
- Isolate resistant to one of 1st line agents (INH, RIF, PZA, EMB, or streptomycin)

Multidrug-Resistant TB (MDR-TB)
- Isolate resistant to at least INH and RIF

Extensively Drug-Resistant TB (XDR-TB)
- Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both

23
Q

Clinical Suspicion for Resistance:

A

Previous treatment for active TB
Intermittent regimen treatment failure in advanced HIV
TB acquisition in high-resistance region
Patient contact with drug-resistant TB
Failure to respond to empiric therapy
Previous FQ therapy for symptoms consistent with CAP later proven to be TB

24
Q

Drug-Resistant Active TB medication groups

A

Group 1
1st line oral drugs (use all possible)
INH, RIF, EMB, PZA

Group 2
Fluoroquinolones (use one)
Levofloxacin, moxifloxacin, ofloxacin

Group 3
Injectable agents (use one)
Capreomycin, kanamycin, amikacin, streptomycin

Group 4
Less effective, 2nd line drugs (use all possible if necessary)
Ethionamide, cycloserine, aminosalicylic acid

Group 5
Less effective or sparse data (use all necessary if < 4 from other groups)
Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin

25
Q

HIV infection with TB- treatment

A

LTBI
INH x9 months preferred
Alternative: INH + rifapentine weekly x12 weeks, if not on ART

Active Disease
INH + rifamycin + EMB + PZA preferred (same as non-HIV)
Rifampin and rifabutin considered comparable; choice based on interactions and cost
CYP450 induction may reduce antiretroviral activity of PIs and NNRTIs
Rifampin ↓ PI levels by up to 95%

26
Q

Immunomodulating Drugs

A

TNF-α inhibitors increase risk of LTBI–> active disease
Screen patients prior to initiation of TNFα inhibitors
LTBI should be treated prior to initiating immunomodulating drugs

27
Q

Pregnancy and TB

A

Delay treatment for LTBI unless:
HIV-positive
Recently infected

Active disease requires treatment:
INH + RIF + EMB x2 months followed by INH + RIF x7 months
PZA –> limited safety data, not recommended in US

Respiratory II Exam 2 (21 decks)

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