anti TB drugs Flashcards
1
Q
TB First line agents
A
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
Streptomycin (Resistance is an isssue considered 3rd line)
2
Q
Second and Third Line TB agents
A
Ethionamide
Capreomycin
Cycloserine
Aminosalicylic Acid (PAS)
Kanamycin &Amikacin
Fluoroquinolones
Linezolid
Rifabutin
Rifapentine
Bedaquiline
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
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
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)
6
Q
TB Transmission
A
Transmission: airborne route
- Droplet nuclei expelled into air when a patient with pulmonary TB coughs, talks, sings, or sneezes
7
Q
TB possible outcomes
A
- Immediate clearance of organism
- Primary disease
- Latent infection
- Reactivation disease
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
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
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
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
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
13
Q
Rifampin (RIF) Resistance
A
Resistance:
- Reduced binding affinity to RNA polymerase -> point mutations within rpoB gene
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
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
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)
17
Q
Pyrazinamide Resistance
A
Resistance:
- Impaired uptake of pyrazinamide
- Impaired biotransformation, mutation in pncA
18
Q
Pyrazinamide ADRs
A
ADRs:
- Hepatotoxicity (1-5%)
- GI upset
- Hyperuricemia
- Also, most common cause of drug rash among first line agents
19
Q
Ethambutol MOA
A
MOA: disrupts synthesis of arabinoglycan
- Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
20
Q
Ethambutol (EMB) Resistsance
A
- Overexpression of emb gene products
- Mutation in embB gene
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
22
Q
Streptomycin MOA
A
MOA: irreversible inhibitor of protein synthesis
- Binds S12 ribosomal protein of 30S subunit
23
Q
Streptomycin Resistance
A
Resistance:
- Mutations in rpsL or rrs gene which alter binding site
24
Q
Streptomycin ADRs
A
ADRs:
- Ototoxicity (vertigo and hearing loss)
- Nephrotoxicity
- Relatively contraindicated in pregnancy (newborn deafness)
25
Approved drugs for TB and MOAs
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
26
**Mechanisms of Mycobacterial Resistance**
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)
27
Antimycobacterial Drugs ADRs
Hepatotoxicity
* 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
Antimycobacterial Drugs ADRs
ocular toxicity
**Ocular Toxicity**
* May be due to EMB
29
Antimycobacterial Drugs ADRs
Rash
**Rash**:
* All agents may cause rash
* Minor pruritic rashes – antihistamines + continuation of drug therapy
* Petechial rash + thrombocytopenia – discontinue rifampin, sign of hypersensitivity reaction
30
Clinical Presentation
Signs and Sx's of TB
**Signs and Sx's of TB**
* Weight loss
* Fatigue
* Productive cough
* Fever
* Night sweats
* Frank hemoptysis
31
Clinical Presentation
TB CXR
**TB CXR**
* Patchy or nodular infiltrates
* Cavitation
32
General Approach for outcomes in treating TB
**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
General Approach w/TB infection
**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
Directly Observed Therapy (DOT)
Compared to self-administration:
Compared to self-administration:
* Decreases drug resistance, relapse rates, mortality
* Improves cure rates
35
Directly Observed Therapy (DOT) recommended for:
**Recommended for those:**
* With drug-resistant infections
* Receiving intermittent regimens
* With HIV
* And children
36
Combination Drug Therapy
Drug resistant mutants
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
Combination Drug Therapy, Drug Resistance
**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
Combination Drug Therapy
Prevention of Resistance
**_2+ active agents should always be used for active TB to prevent resistance_**
39
Combination Drug Therapy
most active anti-TB drugs
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
Combination Drug Therapy
isoniazid/rifampin Combo Effectiveness
* Combination (x9 months) cures 95-98% of susceptible TB cases
* Regimens without a rifamycin are less effective
41
Combination Drug Therapy
INH and RIF, and a 3rd agent
* Adding PZA for first 2 months allows for 6 months total duration
* Once susceptibility known, discontinue ethambutol from the 4 drug regimen
42
Latent Tuberculosis Infection (LTBI) Lifetime Risks
Latent TB infection - 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
Testing that needs to be performed
Drug susceptibility on initial isolate for all patients with active TB
45
Active TB Disease Standard of therapy
**Standard of therapy includes:**
* Initial phase – 2 months
* Continuation phase – 4 or 7 months
46
Active TB Disease patient monitoring
**Active TB Disease patient monitoring:**
* Adverse reactions
* Adherence
* Response to treatment
47
Active TB Disease Initial Phase:
**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 TB Disease Initial Phase Positive Test Results:
* When susceptibility to INH, RIF, or PZA documented – may discontinue EMB
* Those who cannot take PZA should receive INH, RIF, and EMB
49
Active TB Disease Continuation Phase:
**Two factors which increase risk of treatment failure –**
* Cavitary disease at presentation
* Positive sputum culture at 2 months
50
Active TB Disease Continuation Phase:
0-1 Risk Factors
0-1 risk factor: INH + RIF x 4 months (6 months total)
51
Active TB Disease Continuation Phase:
2 Risk Factors
2 risk factors: continuation phase x 7 months (9 months total)
52
Drug-Resistant Active TB
Drug-Resistant TBIsolate resistant to one of 1st line agents (INH, RIF, PZA, EMB, or streptomycin)
53
Drug-Resistant Active TB
Multi-Drug Resistant TB
Multi-Drug Resistant TB (MDR-TB)
Isolate resistant to at least INH and RIF - treat with first, 2nd and possibly 3rd group drugs
54
Drug-Resistant Active TB
Extensively Drug-Resistant TB (XDR-TB)
Extensively Drug-Resistant TB (XDR-TB)
* Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both
55
Drug-Resistant Active TB
Clinical Suspicion for Resistance:
**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
Drug-Resistant Active TB Groups
How many?
Groups 1-5
57
Drug-Resistant Active TB Group 1
Drug-Resistant Active TB Group 1
* 1st line oral drugs (use all possible)
* -INH, RIF, EMB, PZA
58
Drug-Resistant Active TB Group 2
**Drug-Resistant Active TB Group 2**
Fluoroquinolones (use one)
* Levofloxacin, moxifloxacin, ofloxacin
59
Drug-Resistant Active TB Group 3
**Drug-Resistant Active TB Group 3**
Injectable agents (use one)
* Capreomycin, kanamycin, amikacin, streptomycin
60
Drug-Resistant Active TB Group 4
**Drug-Resistant Active TB Group 4**
Less effective, 2nd line drugs (use all possible if necessary)
* Ethionamide, cycloserine, aminosalicylic acid
61
Drug-Resistant Active TB Group 5
**Drug-Resistant Active TB Group 5**
* Less effective or sparse data (use all necessary if Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin
62
HIV Infection LTBI/Latent TB Infection and HIV coinfection
**HIV Infection LTBI/Latent TB Infection and HIV coinfection**
* INH x9 months preferred
* Alternative: INH + rifapentine weekly x12 weeks, if not on ART
63
TB and HIV coinfection Active Disease
**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
Immunomodulating Drugs
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
Pregnancy and LTBI
**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
Mechanisms of Action
67
Mechanisms of Resistance
