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Tuberculosis Flashcards

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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
ADRs with 1st-line agents are common
Hepatotoxicity Ocular Toxicity Rash
26
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 ```
27
ADRs with 1st-line agents are common Ocular Toxicity
May be due to EMB
28
ADRs with 1st-line agents are common Rash
All agents may cause rash  Minor pruritic rashes –antihistamines + continuation of drug therapy  Petechial rash + thrombocytopenia –discontinue rifampin
29
Clinical Presentation Signs/symptoms
``` Weight loss Fatigue Productive cough Fever Night sweats Frank hemoptysis ```
30
Clinical Presentation chest radiograph
Patchy or nodular infiltrates  Cavitation
31
General Approach | Outcomes
``` 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
General Approach | Approach
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
Directly Observed Therapy (DOT) Compared to self-administration:
Decreases drug resistance, relapse rates, mortality | Improves cure rates
34
Directly Observed Therapy (DOT) Recommended for those:
With drug-resistant infections Receiving intermittent regimens With HIV And children
35
Combination Drug Therapy | Drug resistant mutants –1 bacillus in 106
Asymptomatic patients –bacillary load of 103 Cavitarypulmonary TB –bacillary load > 108 Resistance readily selected out if single drug used
36
Combination Drug Therapy | Combination therapy, drug resistance –1 bacillus in 1012
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
2+ active agents should always be used for active TB to prevent
resistance
38
Combination Drug Therapy | Most active anti-TB drugs =
INH and RIF Combination (x9 months) cures 95-98% of susceptible TB cases Regimens without a rifamycinare less effective
39
Adding PZA for first 2 months allows for
6 months total duration
40
Once susceptibility known, discontinue
ethambutol from the 4 drug regimen
41
Mechanisms of Mycobacterial resistance
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
Latent Tuberculosis Infection (LTBI)
Lifetime risk of active disease reduced from 10% to 1% with treatment
43
Latent Tuberculosis Infection (LTBI) Treatment options
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
Active Disease
Drug susceptibility on initial isolate for all patients with active TB
45
Active Disease Standard of therapy includes:
Initial phase –2 months | Continuation phase –4 or 7 months
46
Active Disease Patient monitoring:
Adverse reactions Adherence Response to treatment
47
Active Disease 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
Active Disease Continuation phase
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
Drug-Resistant TB
Isolate resistant to one of 1stline agents (INH, RIF, PZA, EMB, or streptomycin)
50
Multidrug-Resistant TB (MDR-TB)
Isolate resistant to at least INH and RIF
51
Extensively Drug-Resistant TB (XDR-TB)
Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both
52
Drug-Resistant Active TB | 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
53
Drug-Resistant Active TB Group 1
1stline oral drugs (use all possible) | INH, RIF, EMB, PZA
54
Drug-Resistant Active TB Group 2
Fluoroquinolones (use one) | Levofloxacin, moxifloxacin, ofloxacin
55
Drug-Resistant Active TB Group 3
``` Injectable agents (use one) Capreomycin, kanamycin, amikacin, streptomycin ```
56
Drug-Resistant Active TB Group 4
Less effective, 2ndline drugs (use all possible if necessary) Ethionamide, cycloserine, aminosalicylic acid
57
Drug-Resistant Active TB Group 5
Less effective or sparse data (use all necessary if
58
HIV Infection LTBI
INH x9 months preferred | Alternative: INH + rifapentine weekly x12 weeks, if not on ART
59
HIV Infection 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%
60
Immunomodulating Drugs
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
Immunomodulating drugs warnings
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
Pregnancy | Delay treatment for LTBI unless:
HIV-positive | Recently infected
63
Pregnancy | Active disease requires treatment:
INH + RIF + EMB x2 months followed by INH + RIF x7 months | PZA >limited safety data, not recommended in US
64
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?
all four of first line agents
65
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?
yes alcohol for increased hepatotoxicity, drugs, malnutrition for peripheral neuropathy (vit b def so use pyradoxine)
66
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?
we wan to use refabutin bc he is hiv positive and may be on a protease inhibitor if not us rifampin

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