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Respiratory II - Exam 2 > 10-14 TB Drugs - Waller > Flashcards

10-14 TB Drugs - Waller Flashcards

1
Q

How endemic is TB? How many illnesses and deaths annually?

A

—Mycobacterium tuberculosis

—1/3 of world’s population infected with TB

—2nd most common infectious cause of death

—2013 – 9 million illnesses, 1.5 million deaths

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2
Q

What are the major characteristics of TB as an organism? What is the cell envelope and growth rate like?

A

—Acid-fast bacillus (AFB)

—Cell envelope – three macromolecules (peptidoglycan, arabinogalactan, and mycolic acids) linked to lipoarabinomannan (lipopolysaccharide)

—Slow growth rate

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3
Q

How many TB cases in the US in 2014?

A

9,000+

(9421 exactly)

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4
Q

How many days of meds does a typical TB case in the US require? What other medical services does it require?

A

180 days of meds

plus:

  • X-rays
  • lab tests
  • f/u and testing of contacts
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5
Q

How is TB spread?

A

—Transmission: airborne route

—Droplet nuclei expelled into air when a patient with pulmonary TB coughs, talks, sings, or sneezes

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6
Q

What are the possible outcomes of initial disease with TB?

A

—Immediate clearance of organism

—Primary disease

—Latent infection

—Reactivation disease

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7
Q

What drugs are the first-line agents for TB?

A

—Isoniazid (INH)

—Rifampin

—Pyrazinamide

—Ethambutol

—Streptomycin (now often considered 3rd line, resistance is widespread)

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8
Q

What drugs are second or third line agents for TB?

A
  1. —Ethionamide
  2. —Capreomycin
  3. —Cycloserine
  4. —Aminosalicylic Acid (PAS)
  5. —Kanamycin & Amikacin
  6. —Fluoroquinolones
  7. —Linezolid
  8. —Rifabutin
  9. —Rifapentine
  10. —Bedaquiline
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9
Q

What is the MOA for isoniazid/INH?

A

—MOA: inhibits synthesis of mycolic acids

drug that is initially taken is the prodrug (has to be activated before it works)

—Prodrug diffuses into bacilli, activated by KatG enzyme

—Active/radicalized form binds AcpM and KasA

  • inhibits mycolic acid synthesis
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10
Q

How does TB become resistant to isoniazid?

A

—Resistance:

—Mutation or deletion of katG gene (prodrug is no longer activated)

—Overexpression of inhA and ahpC (both are genes for products that inhibit isoniazid)

—Mutation in kasA

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11
Q

How is isoniazid hepatoxic?

A

Phase II and phase I metabolites in the host are mostly renal excretion

  • metabolites not eliminated by kidneys after phase I can acetylate macromolecules/proteins and become hepatotoxic

Slow acetylators for phase I will have more hepatotoxicity

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12
Q

What are the ADRs for isoniazid?

What is one thing you can give patients to help alleviate two of the ADR’s?

A

—ADRs:

—Hepatotoxicity:

  • —Minor elevations in LFTs (10-20%)

— - Clinical hepatitis (1%)

—Peripheral neuropathy - esp in patients already at risk, slow acetylators. Supplement with pyridoxine/vitamin B6 to prevent this.

—CNS toxicity (memory loss, psychosis, seizures)

—Fever, skin rashes, drug-induced SLE - also reduced by pyroxidine supplements

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13
Q

What is the MOA for rifampin? Which stages of TB infection is rifampin effective at?

A

—MOA: inhibits RNA synthesis

—Binds B-subunit of DNA-dependent RNA polymerase (rpoB)

Rifampin can target intracellular, dormant, and active TB bacilli

  • very effective
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14
Q

How does TB become resistant to rifampin?

A

—Resistance:

—Reduced binding affinity to RNA polymerase

  • point mutations within rpoB gene
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15
Q

What are the ADRs associated with rifampin/RIF?

A

—Nausea/vomiting (1.5%)

—Rash (0.8%)

—Fever (0.5%)

—Harmless red/orange color to secretions - will discolor contact lenses

—Hepatotoxicity

—Flu-like syndrome (20%) in those treated < 2x/week (Rif mus be given frequently)

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16
Q

What are the DDIs associated with RIF?

A

—Induces CYPs 1A2, 2C9, 2C19, and 3A4

  • i.e. will decrease warfarin efficacy and INR
  • if someone is on warfarin, readjust dose if anticoag therapy is d/c’ed
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17
Q

What is the MOA for Pyrazinamide?

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

(needs to be protonated to cause therapeutic effect)

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18
Q

How does TB become resistant to Pyrazinamide? 2

A

—Resistance:

  1. Impaired uptake of pyrazinamide
  2. —Impaired biotransformation, mutation in pncA
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19
Q

What are the ADRs associated with Pyrazinamide?

A

—Hepatotoxicity (1-5%)

—GI upset

—Hyperuricemia

Also, most common cause of drug rash among first line agents

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20
Q

What is the MOA for ethambutol?

A

—MOA: disrupts synthesis of arabinoglycan

  • —Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
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21
Q

How does TB become resistsant to ethambutol/EMB?

A

—Overexpression of emb gene products

—Mutation in embB gene

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22
Q

What are the ADRs associated with ethambutol?

A

—Retrobulbar neuritis (loss of visual acuity, red-green color blindness)

(avoid use in people with red/green color blindness, makes it hard to assess ADRs)

—Rash

—Drug fever

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23
Q

What is the MOA for streptomycin?

A

—MOA: irreversible inhibitor of protein synthesis

—Binds S12 ribosomal protein of 30S subunit

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24
Q

How does TB become resistant to streptomycin?

A

—Resistance:

—Mutations in rpsL or rrs gene which alter binding site

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25
Q

What are the ADRs associated with streptomycin?

A

—ADRs:

—Ototoxicity (vertigo and hearing loss)

—Nephrotoxicity

—Relatively contraindicated in pregnancy (newborn deafness)

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26
Q

Again, what are the 8 approved drugs for TB and what is their MOA?

A
  1. Fluoroquinolone - inhibits DNA synthesis and supercoiling by targeting topoisomerase
  2. Rifamycin - inhibits RNA synthesis by targeting RNA polymerase
  3. Streptomycin - inhibits protein synthesis by targeting the 30s ribosomal subunit
  4. Macrolides - target 23S ribosomal RNA, inhibiting peptidyl transferase

5 & 6. Isoniazid and Ethionamide - inhibits mycolic acid synthesis

  1. Ethambutol - inhibits cell wall synthesis
  2. Pyrazinamide - inhibits cell membrane synthesis
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27
Q

Again, what are the 7 mechanisms of mycobacterial resistance?

A
  1. Drug unable to penetrate cell wall
  2. Anaerobic conditions lead to dormant/non-replicating state: drugs that block metabolic processes have no effect during state of dormancy (exceptions include rifamycin and fluoroquinolones)
  3. Alteration of enzym prevents conversion of pro-drug to active form (pyrazinamide, isoniazid)
  4. Alteration of target protein structure prevents drug recognition (rifamycin, ethm=ambutol, streptomycin, fluoroquinolone, macrolide)
  5. Mutations in DNA repair genes lead to mult. drug resistance
  6. Drug exported from cell before it reaches target ( streptomycin, isoniazid, ethambutol)
  7. Low pH renders drug inactive (streptomycin)
28
Q

Which first line drugs cause hepatotoxicity?

A

—May be caused by INH, RIF, or PZA

—Asymptomatic increase in AST (20%)

—Hepatitis (AST ≥ 3 ULN + symptoms or ≥ 5 ULN +/- symptoms) – discontinue

If hepatitis sets in, stop first line drugs then gradually add back in first line drugs until culprit is found

29
Q

Which first line drugs cause ocular toxicity?

A

ethambutol

30
Q

Which first-line drugs cause rash?

In what case of rash do you continue therapy?

In what case of rash do you discontinue?

A

—All agents may cause rash

—Minor pruritic rashes – antihistamines + continuation of drug therapy

—Petechial rash + thrombocytopenia – discontinue rifampin, sign of hypersensitivity reaction

31
Q

What are the signs and Sx’s of TB?

A

—Weight loss

—Fatigue

—Productive cough

—Fever

—Night sweats

—Frank hemoptysis

32
Q

What will TB show on CXR?

A

—Patchy or nodular infiltrates

—Cavitation

33
Q

What are the best outcomes/goals for treating a TB infection?

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)

34
Q

What approach is used to achieve treatment goals with TB infection?

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 of care

  • add on 2-3 agents at a time to a failing TB regimen
35
Q

What is directly observed therapy (DOT)?

A

—Compared to self-administration:

—Decreases drug resistance, relapse rates, mortality

—Improves cure rates

36
Q

What types of infections is DOT recommended for?

A

—Recommended for those:

—With drug-resistant infections

—Receiving intermittent regimens

—With HIV

—And children

37
Q

Why do active TB infections become AB resistant so readily? Why not asymptomatic patients?

A

—Drug resistant mutants – 1 bacillus in 106

—Asymptomatic patients – bacillary load of 103

—Cavitary pulmonary TB – bacillary load > 108

—Resistance readily selected out if single drug used

38
Q

Why is combination therapy so useful in treating active TB infections?

A

——Combination therapy, drug resistance – 1 bacillus in 1012

—Rates of resistance additive functions of individual rates

—Example: only 1 in 1013 organisms would be naturally resistant to both isoniazid (1 in 106) and rifampin (1 in 107)

39
Q

How many agents should ALWAYS be used for active TB to prevent resistance?

A

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

40
Q

Which are the most active anti-TB drugs?

A

INH and RIF

  • always give rifamycin or rifampin… unless thrombocytopenia + petechial rash… in which case discontinue rifampin.
41
Q

How effective are isoniazid and rifampin together?

A

—Combination (x9 months) cures 95-98% of susceptible TB cases

—Regimens without a rifamycin are less effective

42
Q

In addition to INH and RIF, what other drugs should be added to combination therapy, and when?

A

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

—Once susceptibility known, discontinue ethambutol from the 4 drug regimen

43
Q

How is lifetime risk of conversion from latent to active TB changed with treatment?

A

Latent TB infection - —lifetime risk of active disease reduced from 10% to 1% with treatment

44
Q

What are the treatment options for a latent TB infection?

A

—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

45
Q

What type of testing should you do with all patients with active TB?

A

Drug susceptibility testing on initial isolate

46
Q

What is the standard of therapy timeline for active TB?

A

—Standard of therapy includes:

—Initial phase – 2 months

—Continuation phase – 4 or 7 months

47
Q

What should be included under patient monitoring in active TB?

A

—Adverse reactions

—Adherence

—Response to treatment

48
Q

What is the initial treatment for active TB before susceptibility testing results are back?

A

—Until susceptibility available – INH + RIF + EMB + PZA

49
Q

What should you do with initial treatment for active TB after susceptibility testing is back?

A

—When susceptibility to INH, RIF, or PZA documented – may discontinue EMB

—Those who cannot take PZA should receive INH, RIF, and EMB

50
Q

What are 2 factors that increase risk of Tx failure for active TB?

A

—Cavitary disease at presentation

—Positive sputum culture at 2 months

51
Q

If someone has a 0-1 risk factors that increase risk of Tx failure for active TB, what should continuation treatment be?

A

—0-1 risk factor: INH + RIF x 4 months (6 months total)

52
Q

If someone has 2 risk factors that increase risk of Tx failure for active TB, what should continuation treatment be?

A

—2 risk factors: continuation phase x 7 months (9 months total)

53
Q

What is drug-resistant TB?

A

—Drug-Resistant TB

—Isolate resistant to one of 1st line agents (INH, RIF, PZA, EMB, or streptomycin)

54
Q

What is multi-drug resistant TB?

A

—(MDR-TB)

—Isolate resistant to at least INH and RIF

  • treat with first, 2nd and possibly 3rd group drugs
55
Q

What is extensively drug-resistant TB?

A

—(XDR-TB)

—Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both

56
Q

What factors increase suspicion for resistant TB?

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

57
Q

How many groups of treatment options are there for drug-resistant active TB?

A

Groups 1-5

58
Q

What are group 1 drugs for drug-resistant active TB?

A

—1st line oral drugs (use all possible)

—INH, RIF, EMB, PZA

59
Q

What are group 2 drugs for drug-resistant active TB?

A

—Fluoroquinolones (use one)

—Levofloxacin, moxifloxacin, ofloxacin

60
Q

What are group 3 drugs for drug-resistant active TB?

A

—Injectable agents (use one)

—Capreomycin, kanamycin, amikacin, streptomycin

61
Q

What are group 4 drugs for drug-resistant active TB?

A

—Less effective, 2nd line drugs (use all possible if necessary)

—Ethionamide, cycloserine, aminosalicylic acid

62
Q

What are group 5 drugs for drug-resistant active TB?

A

—Less effective or sparse data (use all necessary if < 4 from other groups)

—Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin

63
Q

Which drugs are used for LTBI/Latent TB Infection and HIV coinfection?

A

—INH x9 months preferred

—Alternative: INH + rifapentine weekly x12 weeks, if not on ART

64
Q

Which drugs are used for active TB and HIV coinfection?

A

—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%

65
Q

What should be treated before using immunomodulating drugs? Why?

A

—LTBI should be treated prior to initiating immunomodulating drugs

—TNF-α inhibitors increase risk of LTBI developing into active disease

—Screen patients prior to initiation of TNFα inhibitors

66
Q

What should you do with pregnant patients with 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 à limited safety data, not recommended in US

67
Q
A

Respiratory II - Exam 2 (13 decks)

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