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Respiratory II > anti TB drugs > Flashcards

anti TB drugs Flashcards

1
Q

TB First line agents

A

—Isoniazid (INH)—

Rifampin—

Pyrazinamide—

Ethambutol—

Streptomycin (Resistance is an isssue considered 3rd line)

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2
Q

Second and Third Line TB agents

A

—Ethionamide —

Capreomycin —

Cycloserine —

Aminosalicylic Acid (PAS) —

Kanamycin &Amikacin —

Fluoroquinolones —

Linezolid —

Rifabutin —

Rifapentine —

Bedaquiline

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3
Q

Tuberculosis (TB) Overview

A

—Mycobacterium tuberculosis:

  • —2nd most common infectious cause of death —
  • 2013 – 9 million illnesses, 1.5 million deaths
  • 1/3 of world’s population infected with TB—
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4
Q

TB Characteristics

A
  • —Cell envelope – three macromolecules (peptidoglycan, arabinogalactan, and mycolic acids) linked to lipoarabinomannan (lipopolysaccharide)
  • Acid-fast bacillus (AFB)—
  • Slow growth rate
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5
Q

TB in the US in 2014

A

Cases: 9421

Cost: $435 million

Time: 180 days of meds (as well as X-rays-lab tests- f/u and testing of contacts)

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6
Q

TB Transmission

A

—Transmission: airborne route

  • Droplet nuclei expelled into air when a patient with pulmonary TB coughs, talks, sings, or sneezes
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7
Q

TB possible outcomes

A
  • Immediate clearance of organism—
  • Primary disease —
  • Latent infection—
  • Reactivation disease
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8
Q

Isoniazid (INH) MOA

A

—MOA: inhibits synthesis of mycolic acidsdrug 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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9
Q

Isoniazid (INH) Resistance:

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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10
Q

Isoniazid (INH) ADRs

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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11
Q

Isoniazid (INH) ADRs

hepatoxicity

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

Rifampin (RIF) MOA

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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13
Q

Rifampin (RIF) Resistance

A

—Resistance:—

  • Reduced binding affinity to RNA polymerase -> point mutations within rpoB gene
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14
Q

Rifampin (RIF) ADRs

A

—ADRs:

  • 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
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15
Q

Rifampin (RIF) DDIs

A

—DDIs:

Induces CYPs 1A2, 2C9, 2C19, and 3A4.

will decrease warfarin efficacy and INR - if someone is on warfarin, readjust dose if anticoag therapy is discontinued

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16
Q

Pyrazinamide MOA

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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17
Q

Pyrazinamide Resistance

A

—Resistance:

  • Impaired uptake of pyrazinamide
  • —Impaired biotransformation, mutation in pncA
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18
Q

Pyrazinamide ADRs

A

—ADRs:

  • Hepatotoxicity (1-5%)—
  • GI upset—
  • Hyperuricemia
  • Also, most common cause of drug rash among first line agents
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19
Q

Ethambutol MOA

A

—MOA: disrupts synthesis of arabinoglycan

  • —Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
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20
Q

Ethambutol (EMB) Resistsance

A
  • —Overexpression of emb gene products—
  • Mutation in embB gene
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21
Q

Ethambutol (EMB) ADRs

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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22
Q

Streptomycin MOA

A

—MOA: irreversible inhibitor of protein synthesis—

  • Binds S12 ribosomal protein of 30S subunit
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23
Q

Streptomycin Resistance

A

—Resistance:

  • —Mutations in rpsL or rrs gene which alter binding site
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24
Q

Streptomycin ADRs

A

—ADRs:—

  • Ototoxicity (vertigo and hearing loss)—
  • Nephrotoxicity
  • —Relatively contraindicated in pregnancy (newborn deafness)
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25
Q

Approved drugs for TB and MOAs

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. Isoniazid - inhibits mycolic acid synthesis
  6. Ethionamide - inhibits mycolic acid synthesis
  7. Ethambutol - inhibits cell wall synthesis
  8. Pyrazinamide - inhibits cell membrane synthesis
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26
Q

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)
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27
Q

Antimycobacterial Drugs ADRs

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
28
Q

Antimycobacterial Drugs ADRs

ocular toxicity

A

—Ocular Toxicity

  • —May be due to EMB
29
Q

Antimycobacterial Drugs ADRs

Rash

A

Rash:

  • —All agents may cause rash—
  • Minor pruritic rashes – antihistamines + continuation of drug therapy—
  • Petechial rash + thrombocytopenia – discontinue rifampin, sign of hypersensitivity reaction
30
Q

Clinical Presentation

Signs and Sx’s of TB

A

—Signs and Sx’s of TB

  • Weight loss—
  • Fatigue—
  • Productive cough—
  • Fever—
  • Night sweats—
  • Frank hemoptysis
31
Q

Clinical Presentation

TB CXR

A

—TB CXR

  • Patchy or nodular infiltrates—
  • Cavitation
32
Q

General Approach for outcomes in treating TB

A

—outcomes in treating TB

  • 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)
33
Q

General Approach w/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
34
Q

Directly Observed Therapy (DOT)

—Compared to self-administration:

A

—Compared to self-administration:

  • —Decreases drug resistance, relapse rates, mortality
  • —Improves cure rates
35
Q

Directly Observed Therapy (DOT) recommended for:

A

—Recommended for those:

  • —With drug-resistant infections—
  • Receiving intermittent regimens
  • —With HIV—
  • And children
36
Q

Combination Drug Therapy

Drug resistant mutants

A

—Drug resistant mutants – 1 bacillus in 10^6—

  • Asymptomatic patients – bacillary load of 103—
  • Cavitary pulmonary TB – bacillary load > 108—
  • Resistance readily selected out if single

drug used

37
Q

Combination Drug Therapy, Drug Resistance

A

——Combination therapy, drug resistance – 1 bacillus in 10^12—

  • Rates of resistance additive functions of individual rates—
  • Example: only 1 in 1013 organisms would be naturally resistant to both isoniazid (1 in 10^6) and rifampin (1 in 10^7)
38
Q

Combination Drug Therapy

Prevention of Resistance

A

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

39
Q

Combination Drug Therapy

most active anti-TB drugs

A

Most active anti-TB drugs = INH and RIF - always give rifamycin or rifampin… unless thrombocytopenia + petechial rash… in which case discontinue rifampin.

  • —Combination (x9 months) cures 95-98% of susceptible TB cases
  • —Regimens without a rifamycin are less effective
40
Q

Combination Drug Therapy

isoniazid/rifampin Combo Effectiveness

A
  • —Combination (x9 months) cures 95-98% of susceptible TB cases—
  • Regimens without a rifamycin are less effective
41
Q

Combination Drug Therapy

INH and RIF, and a 3rd agent

A
  • —Adding PZA for first 2 months allows for 6 months total duration
  • —Once susceptibility known, discontinue ethambutol from the 4 drug regimen
42
Q

Latent Tuberculosis Infection (LTBI) Lifetime Risks

A

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

43
Q

Latent Tuberculosis Infection (LTBI) Treatment Options

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
44
Q

Active Disease

Testing that needs to be performed

A

—Drug susceptibility on initial isolate for all patients with active TB

45
Q

Active TB Disease Standard of therapy

A

—Standard of therapy includes:

  • —Initial phase – 2 months—
  • Continuation phase – 4 or 7 months
46
Q

Active TB Disease patient monitoring

A

—Active TB Disease patient monitoring:

  • Adverse reactions—
  • Adherence—
  • Response to treatment
47
Q

—Active TB Disease Initial Phase:

A

——Initial Phase:

  • 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
48
Q

—Active TB Disease Initial Phase Positive Test Results:

A
  • —When susceptibility to INH, RIF, or PZA documented – may discontinue EMB
  • —Those who cannot take PZA should receive INH, RIF, and EMB
49
Q

—Active TB Disease Continuation Phase:

A

——Two factors which increase risk of treatment failure –

  • Cavitary disease at presentation—
  • Positive sputum culture at 2 months
50
Q

Active TB Disease Continuation Phase:

0-1 Risk Factors

A

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

51
Q

Active TB Disease Continuation Phase:

2 Risk Factors

A

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

52
Q

Drug-Resistant Active TB

A

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

53
Q

Drug-Resistant Active TB

Multi-Drug Resistant TB

A

—Multi-Drug Resistant TB (MDR-TB)

—Isolate resistant to at least INH and RIF - treat with first, 2nd and possibly 3rd group drugs

54
Q

Drug-Resistant Active TB

—Extensively Drug-Resistant TB (XDR-TB)

A

——Extensively Drug-Resistant TB (XDR-TB)

  • —Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both
55
Q

Drug-Resistant Active TB

—Clinical Suspicion for Resistance:

A

——Clinical Suspicion for Resistance:

  • 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
56
Q

Drug-Resistant Active TB Groups

How many?

A

Groups 1-5

57
Q

Drug-Resistant Active TB Group 1

A

Drug-Resistant Active TB Group 1

  • 1st line oral drugs (use all possible)
  • -—INH, RIF, EMB, PZA
58
Q

Drug-Resistant Active TB Group 2

A

—Drug-Resistant Active TB Group 2

Fluoroquinolones (use one)—

  • Levofloxacin, moxifloxacin, ofloxacin
59
Q

Drug-Resistant Active TB Group 3

A

—Drug-Resistant Active TB Group 3

Injectable agents (use one)—

  • Capreomycin, kanamycin, amikacin, streptomycin
60
Q

Drug-Resistant Active TB Group 4

A

—Drug-Resistant Active TB Group 4

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

  • Ethionamide, cycloserine, aminosalicylic acid
61
Q

Drug-Resistant Active TB Group 5

A

—Drug-Resistant Active TB Group 5

  • Less effective or sparse data (use all necessary if —Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin
62
Q

HIV Infection LTBI/Latent TB Infection and HIV coinfection

A

—HIV Infection LTBI/Latent TB Infection and HIV coinfection

  • INH x9 months preferred—
  • Alternative: INH + rifapentine weekly x12 weeks, if not on ART
63
Q

TB and HIV coinfection Active Disease

A

—TB and HIV coinfection 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%
64
Q

Immunomodulating Drugs

A

—TNF-α inhibitors increase risk of LTBI à active disease

  • —Screen patients prior to initiation of TNFα inhibitors
  • —LTBI should be treated prior to initiating immunomodulating drugs
65
Q

Pregnancy and LTBI

A

—Pregnancy and LTBI:

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
66
Q

Mechanisms of Action

A
67
Q

Mechanisms of Resistance

A

Respiratory II (14 decks)

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