10-14 TB Drugs - Waller Flashcards
How endemic is TB? How many illnesses and deaths annually?
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
What are the major characteristics of TB as an organism? What is the cell envelope and growth rate like?
Acid-fast bacillus (AFB)
Cell envelope – three macromolecules (peptidoglycan, arabinogalactan, and mycolic acids) linked to lipoarabinomannan (lipopolysaccharide)
Slow growth rate
How many TB cases in the US in 2014?
9,000+
(9421 exactly)
How many days of meds does a typical TB case in the US require? What other medical services does it require?
180 days of meds
plus:
- X-rays
- lab tests
- f/u and testing of contacts
How is TB spread?
Transmission: airborne route
Droplet nuclei expelled into air when a patient with pulmonary TB coughs, talks, sings, or sneezes
What are the possible outcomes of initial disease with TB?
Immediate clearance of organism
Primary disease
Latent infection
Reactivation disease
What drugs are the first-line agents for TB?
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
Streptomycin (now often considered 3rd line, resistance is widespread)
What drugs are second or third line agents for TB?
- Ethionamide
- Capreomycin
- Cycloserine
- Aminosalicylic Acid (PAS)
- Kanamycin & Amikacin
- Fluoroquinolones
- Linezolid
- Rifabutin
- Rifapentine
- Bedaquiline
What is the MOA for isoniazid/INH?
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
How does TB become resistant to isoniazid?
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
How is isoniazid hepatoxic?
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
What are the ADRs for isoniazid?
What is one thing you can give patients to help alleviate two of the ADR’s?
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
What is the MOA for rifampin? Which stages of TB infection is rifampin effective at?
MOA: inhibits RNA synthesis
Binds B-subunit of DNA-dependent RNA polymerase (rpoB)
Rifampin can target intracellular, dormant, and active TB bacilli
- very effective
How does TB become resistant to rifampin?
Resistance:
Reduced binding affinity to RNA polymerase
- point mutations within rpoB gene
What are the ADRs associated with rifampin/RIF?
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)
What are the DDIs associated with RIF?
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
What is the MOA for Pyrazinamide?
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)
How does TB become resistant to Pyrazinamide? 2
Resistance:
- Impaired uptake of pyrazinamide
- Impaired biotransformation, mutation in pncA
What are the ADRs associated with Pyrazinamide?
Hepatotoxicity (1-5%)
GI upset
Hyperuricemia
Also, most common cause of drug rash among first line agents
What is the MOA for ethambutol?
MOA: disrupts synthesis of arabinoglycan
- Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
How does TB become resistsant to ethambutol/EMB?
Overexpression of emb gene products
Mutation in embB gene
What are the ADRs associated with ethambutol?
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
What is the MOA for streptomycin?
MOA: irreversible inhibitor of protein synthesis
Binds S12 ribosomal protein of 30S subunit
How does TB become resistant to streptomycin?
Resistance:
Mutations in rpsL or rrs gene which alter binding site
What are the ADRs associated with streptomycin?
ADRs:
Ototoxicity (vertigo and hearing loss)
Nephrotoxicity
Relatively contraindicated in pregnancy (newborn deafness)
Again, what are the 8 approved drugs for TB and what is their MOA?
- Fluoroquinolone - inhibits DNA synthesis and supercoiling by targeting topoisomerase
- Rifamycin - inhibits RNA synthesis by targeting RNA polymerase
- Streptomycin - inhibits protein synthesis by targeting the 30s ribosomal subunit
- Macrolides - target 23S ribosomal RNA, inhibiting peptidyl transferase
5 & 6. Isoniazid and Ethionamide - inhibits mycolic acid synthesis
- Ethambutol - inhibits cell wall synthesis
- Pyrazinamide - inhibits cell membrane synthesis
Again, what are the 7 mechanisms of mycobacterial resistance?
- Drug unable to penetrate cell wall
- 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)
- Alteration of enzym prevents conversion of pro-drug to active form (pyrazinamide, isoniazid)
- Alteration of target protein structure prevents drug recognition (rifamycin, ethm=ambutol, streptomycin, fluoroquinolone, macrolide)
- Mutations in DNA repair genes lead to mult. drug resistance
- Drug exported from cell before it reaches target ( streptomycin, isoniazid, ethambutol)
- Low pH renders drug inactive (streptomycin)
Which first line drugs cause 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
Which first line drugs cause ocular toxicity?
ethambutol
Which first-line drugs cause rash?
In what case of rash do you continue therapy?
In what case of rash do you discontinue?
All agents may cause rash
Minor pruritic rashes – antihistamines + continuation of drug therapy
Petechial rash + thrombocytopenia – discontinue rifampin, sign of hypersensitivity reaction
What are the signs and Sx’s of TB?
Weight loss
Fatigue
Productive cough
Fever
Night sweats
Frank hemoptysis
What will TB show on CXR?
Patchy or nodular infiltrates
Cavitation
What are the best outcomes/goals for treating a TB infection?
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)
What approach is used to achieve treatment goals with 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
What is directly observed therapy (DOT)?
Compared to self-administration:
Decreases drug resistance, relapse rates, mortality
Improves cure rates
What types of infections is DOT recommended for?
Recommended for those:
With drug-resistant infections
Receiving intermittent regimens
With HIV
And children
Why do active TB infections become AB resistant so readily? Why not asymptomatic patients?
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
Why is combination therapy so useful in treating active TB infections?
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)
How many agents should ALWAYS be used for active TB to prevent resistance?
2+ active agents should always be used for active TB to prevent resistance
Which are the most active anti-TB drugs?
INH and RIF
- always give rifamycin or rifampin… unless thrombocytopenia + petechial rash… in which case discontinue rifampin.
How effective are isoniazid and rifampin together?
Combination (x9 months) cures 95-98% of susceptible TB cases
Regimens without a rifamycin are less effective
In addition to INH and RIF, what other drugs should be added to combination therapy, and when?
Adding PZA for first 2 months allows for 6 months total duration
Once susceptibility known, discontinue ethambutol from the 4 drug regimen
How is lifetime risk of conversion from latent to active TB changed with treatment?
Latent TB infection - lifetime risk of active disease reduced from 10% to 1% with treatment
What are the treatment options for a latent TB infection?
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
What type of testing should you do with all patients with active TB?
Drug susceptibility testing on initial isolate
What is the standard of therapy timeline for active TB?
Standard of therapy includes:
Initial phase – 2 months
Continuation phase – 4 or 7 months
What should be included under patient monitoring in active TB?
Adverse reactions
Adherence
Response to treatment
What is the initial treatment for active TB before susceptibility testing results are back?
Until susceptibility available – INH + RIF + EMB + PZA
What should you do with initial treatment for active TB after susceptibility testing is back?
When susceptibility to INH, RIF, or PZA documented – may discontinue EMB
Those who cannot take PZA should receive INH, RIF, and EMB
What are 2 factors that increase risk of Tx failure for active TB?
Cavitary disease at presentation
Positive sputum culture at 2 months
If someone has a 0-1 risk factors that increase risk of Tx failure for active TB, what should continuation treatment be?
0-1 risk factor: INH + RIF x 4 months (6 months total)
If someone has 2 risk factors that increase risk of Tx failure for active TB, what should continuation treatment be?
2 risk factors: continuation phase x 7 months (9 months total)
What is drug-resistant TB?
Drug-Resistant TB
Isolate resistant to one of 1st line agents (INH, RIF, PZA, EMB, or streptomycin)
What is multi-drug resistant TB?
(MDR-TB)
Isolate resistant to at least INH and RIF
- treat with first, 2nd and possibly 3rd group drugs
What is extensively drug-resistant TB?
(XDR-TB)
Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both
What factors increase suspicion for resistant TB?
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
How many groups of treatment options are there for drug-resistant active TB?
Groups 1-5
What are group 1 drugs for drug-resistant active TB?
1st line oral drugs (use all possible)
INH, RIF, EMB, PZA
What are group 2 drugs for drug-resistant active TB?
Fluoroquinolones (use one)
Levofloxacin, moxifloxacin, ofloxacin
What are group 3 drugs for drug-resistant active TB?
Injectable agents (use one)
Capreomycin, kanamycin, amikacin, streptomycin
What are group 4 drugs for drug-resistant active TB?
Less effective, 2nd line drugs (use all possible if necessary)
Ethionamide, cycloserine, aminosalicylic acid
What are group 5 drugs for drug-resistant active TB?
Less effective or sparse data (use all necessary if < 4 from other groups)
Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin
Which drugs are used for LTBI/Latent TB Infection and HIV coinfection?
INH x9 months preferred
Alternative: INH + rifapentine weekly x12 weeks, if not on ART
Which drugs are used for active TB and HIV coinfection?
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%
What should be treated before using immunomodulating drugs? Why?
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
What should you do with pregnant patients with TB?
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
