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Tuberculosis Flashcards

1
Q

TB first line agents

A 
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
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2
Q

TB Second-Line (and Third-Line) 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
2ndmost 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

Tuberculosis (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

Transmission

A

airborne route

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

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6
Q

Possible outcomes:

A

Immediate clearance of organism
Primary disease
Latent infection
Reactivation disease

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7
Q

Isoniazid (INH)

moa

A

inhibits synthesis of mycolic acids

Prodrug, activated by KatG

Active form binds AcpMand KasA>inhibits mycolic acid synthesis

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8
Q

Isoniazid (INH)

Resistance

A

Mutation or deletion of katGgene
Overexpression of inhAand ahpC
Mutation in kasA

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9
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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10
Q

Rifampin (RIF)

MOA

A

inhibits RNA synthesis

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

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11
Q

Rifampin (RIF)

Resistance

A

Reduced binding affinity to RNA polymerase >point mutations within rpoBgene

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12
Q

Rifampin (RIF)

ADRs

A 
Nausea/vomiting (1.5%)
Rash (0.8%)
Fever (0.5%)
Harmless red/orange color to secretions
Hepatotoxicity
Flu-like syndrome (20%) in those treated
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13
Q

Rifampin (RIF)

DDIs

A

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

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14
Q

Pyrazinamide (PZA)

MOA

A

disrupts mycobacterial cell membrane synthesis and transport functions
Macrophage uptake, conversion to pyrazinoicacid (POA-)
Efflux pump to extracellular milieu
POA-protonated to POAH, reenters bacillus

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15
Q

Pyrazinamide (PZA)

Resistance

A

Impaired biotransformation, mutation in pncA

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16
Q

Pyrazinamide (PZA)

ADRs

A

Hepatotoxicity (1-5%)
GI upset
Hyperuricemia

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17
Q

Ethambutol (EMB)

MOA

A

disrupts synthesis of arabinoglycan

Inhibits mycobacterial arabinosyltransferases (encoded by embCABoperon

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18
Q

Ethambutol (EMB)

Resistance

A

Overexpression of embgene products

Mutation in embBgene

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19
Q

Ethambutol (EMB)

ADRs

A

Retrobulbarneuritis (loss of visual acuity, red-green color blindness)
Rash
Drug fever

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20
Q

Streptomycin

MOA

A

irreversible inhibitor of protein synthesis

Binds S12 ribosomal protein of 30S subunit

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21
Q

Streptomycin

Resistance

A

Mutations in rpsLor rrsgene which alter binding site

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22
Q

Streptomycin

ADRs

A

Ototoxicity (vertigo and hearing loss)
Nephrotoxicity
Relatively contraindicated in pregnancy (newborn deafness)

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23
Q

Antimycobacterial Drugs

Aproved Drugs

A

Fluoroquinolones

Rifamycin

Streptomycin

Macrolides

Isoniazid and ethionamide

Pyrazinamide

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24
Q

Antimycobacterial Drugs

experimental drugs

A

TMC 207

PA 824

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25
Q

ADRs with 1st-line agents are common

A

Hepatotoxicity

Ocular Toxicity

Rash

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26
Q

ADRs with 1st-line agents are common

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
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27
Q

ADRs with 1st-line agents are common

Ocular Toxicity

A

May be due to EMB

28
Q

ADRs with 1st-line agents are common

Rash

A

All agents may cause rash

Minor pruritic rashes –antihistamines + continuation of drug therapy

Petechial rash + thrombocytopenia –discontinue rifampin

29
Q

Clinical Presentation

Signs/symptoms

A 
Weight loss
Fatigue
Productive cough
Fever
Night sweats
Frank hemoptysis
30
Q

Clinical Presentation

chest radiograph

A

Patchy or nodular infiltrates

Cavitation

31
Q

General Approach

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)
32
Q

General Approach

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 of care

33
Q

Directly Observed Therapy (DOT)

Compared to self-administration:

A

Decreases drug resistance, relapse rates, mortality

Improves cure rates

34
Q

Directly Observed Therapy (DOT)

Recommended for those:

A

With drug-resistant infections
Receiving intermittent regimens
With HIV
And children

35
Q

Combination Drug Therapy

Drug resistant mutants –1 bacillus in 106

A

Asymptomatic patients –bacillary load of 103

Cavitarypulmonary TB –bacillary load > 108
Resistance readily selected out if single drug used

36
Q

Combination Drug Therapy

Combination therapy, drug resistance –1 bacillus in 1012

A

Rates of resistance additive functions of individual rates

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

37
Q

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

A

resistance

38
Q

Combination Drug Therapy

Most active anti-TB drugs =

A

INH and RIF
Combination (x9 months) cures 95-98% of susceptible TB cases
Regimens without a rifamycinare less effective

39
Q

Adding PZA for first 2 months allows for

A

6 months total duration

40
Q

Once susceptibility known, discontinue

A

ethambutol from the 4 drug regimen

41
Q

Mechanisms of Mycobacterial resistance

A

drug unable to penetrate cellw all

low ph renders drug inactive (streptomycin)

Mutations in dna repair genes lead to multiple drug resistance

drug exported fro cell before it reaches target (streptomycin, isoniazid, ethambutol)

anaerobic conditions lead to dormant/non-replicating state, drugs that block metabolic processes have no effect during sate of dormancy (exceptions, rifamycin, fluoroquinolone)

Alteration of enzyme prevents conversion of prodrug to active form (pyrazinamide isoniazid)

alteration of target protein structure prevents drug recognition (rifamycin ethambutol, streptomycin fluoroquinolone, macrolide)

42
Q

Latent Tuberculosis Infection (LTBI)

A

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

A

Drug susceptibility on initial isolate for all patients with active TB

45
Q

Active Disease

Standard of therapy includes:

A

Initial phase –2 months

Continuation phase –4 or 7 months

46
Q

Active Disease

Patient monitoring:

A

Adverse reactions
Adherence
Response to treatment

47
Q

Active Disease

Initial Phase

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

48
Q

Active Disease

Continuation phase

A

Two factors which increase risk of treatment failure –
Cavitarydisease at presentation
Positive sputum culture at 2 months

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

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

49
Q

Drug-Resistant TB

A

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

50
Q

Multidrug-Resistant TB (MDR-TB)

A

Isolate resistant to at least INH and RIF

51
Q

Extensively Drug-Resistant TB (XDR-TB)

A

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

52
Q

Drug-Resistant Active TB

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

53
Q

Drug-Resistant Active TB

Group 1

A

1stline oral drugs (use all possible)

INH, RIF, EMB, PZA

54
Q

Drug-Resistant Active TB

Group 2

A

Fluoroquinolones (use one)

Levofloxacin, moxifloxacin, ofloxacin

55
Q

Drug-Resistant Active TB

Group 3

A 
Injectable agents (use one)
Capreomycin, kanamycin, amikacin, streptomycin
56
Q

Drug-Resistant Active TB

Group 4

A

Less effective, 2ndline drugs (use all possible if necessary)
Ethionamide, cycloserine, aminosalicylic acid

57
Q

Drug-Resistant Active TB

Group 5

A

Less effective or sparse data (use all necessary if

58
Q

HIV Infection

LTBI

A

INH x9 months preferred

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

59
Q

HIV Infection

Active Disease

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%

60
Q

Immunomodulating Drugs

A

TNF-αinhibitors increase risk of LTBI >active disease
Screen patients prior to initiation of TNFαinhibitors
LTBI should be treated prior to initiating immunomodulating drugs

61
Q

Immunomodulating drugs warnings

A

increased risk of serious infections leading to hospitalization or death, including TB, bacterial sepsis, invasive fungal infections (histoplasmosis) due to other opportunistic pathogens

Discontinue REMICADE if a patient develops a serious infection

perform test for latent TB if positive start treatment for TB prior to starting Remicade. Monitor all patients for active TB during treatment even if initial latent TB is negative

62
Q

Pregnancy

Delay treatment for LTBI unless:

A

HIV-positive

Recently infected

63
Q

Pregnancy

Active disease requires treatment:

A

INH + RIF + EMB x2 months followed by INH + RIF x7 months

PZA >limited safety data, not recommended in US

64
Q

43 yohomeless male presents to the ED with a 2 month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough.
SH: currently living on the street; has spent time in homeless shelters and prison; drinks 2-3 pints of hard alcohol daily x 15 years; reports IVDU.
CXR: right apical infiltrate
Labs: sputum smear –AFB; rapid HIV antibody test +

What drugs should be started for treatment of presumptive pulmonary TB?

A

all four of first line agents

65
Q

43 yohomeless male presents to the ED with a 2 month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough.
SH: currently living on the street; has spent time in homeless shelters and prison; drinks 2-3 pints of hard alcohol daily x 15 years; reports IVDU.
CXR: right apical infiltrate
Labs: sputum smear –AFB; rapid HIV antibody test +

Does this patient have heightened risk of developing medication toxicity?

A

yes alcohol for increased hepatotoxicity, drugs, malnutrition for peripheral neuropathy (vit b def so use pyradoxine)

66
Q

43 yohomeless male presents to the ED with a 2 month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough.
SH: currently living on the street; has spent time in homeless shelters and prison; drinks 2-3 pints of hard alcohol daily x 15 years; reports IVDU.
CXR: right apical infiltrate
Labs: sputum smear –AFB; rapid HIV antibody test +

If so, which medication(s) would be likely to cause toxicity?

A

we wan to use refabutin bc he is hiv positive and may be on a protease inhibitor if not us rifampin

Resp (11 decks)

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