TB Pharm Flashcards
TB First-Line agents
Isoniazid (INH) Rifampin Pyrazinamide Ethambutol Streptomycin
TB Second-line (and 3rd line) agents
Ethionamide Capreomycin Cycloserine Aminosalicylic Acid (PAS) Kanamycin & Amikacin Fluoroquinolones Linezolid Rifabutin Rifapentine Bedaquiline
Tuberculosis (TB) characteristics
Cell envelope – three macromolecules (peptidoglycan, arabinogalactan, mycolic acids) linked to lipoarabinomannan (lipopolysaccharide)
Acid-fast bacillus (AFB)
Slow growth rate
Natural History of Infection
Transmission: airborne route
- Droplet nuclei expelled into air when a patient with pulmonary TB coughs, sneezes, or spits
Inhalation of droplets leads to 4 possible outcomes:
- Immediate clearance of organism
- Primary disease
- Latent infection
- Reactivation disease
Isoniazid (INH) MOA, Resistance
MOA: inhibits synthesis of mycolic acids
Prodrug, activated by KatG
Active form binds AcpM and KasA –> inhibits mycolic acid synthesis
Resistance:
Mutation or deletion of katG gene
Overexpression of inhA and ahpC
Mutation in kasA
Isoniazid (INH) ADRs
Hepatotoxicity - Minor elevations in LFTs (10-20%) - Clinical hepatitis (1%) Peripheral neuropathy CNS toxicity (memory loss, psychosis, seizures) Fever, skin rashes, drug-induced SLE
Rifampin (RIF) MOA
MOA: inhibits RNA synthesis
Binds B-subunit of DNA-dependent RNA polymerase (rpoB)
Resistance:
Reduced binding affinity to RNA polymerase –> point mutations within rpoB gene
Rifampin (RIF) ADRs/ DDIs
ADRs:
- Nausea/vomiting (1.5%)
- Rash (0.8%)
- Fever (0.5%)
- Harmless red/orange color to secretions
- Hepatotoxicity
- Flu-like syndrome (20%) in those treated < 2x/week
DDIs:
*** Induces CYPs 1A2, 2C9, 2C19, and 3A4
Pyrazinamide (PZA) MOA, resistance, ADRs
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
Resistance:
Impaired biotransformation, mutation in pncA
ADRs:
Hepatotoxicity (1-5%)- perhaps the most hepatotoxic
GI upset
Hyperuricemia
Ethambutol (EMB) MOA, Resistance, ADRs
MOA: disrupts synthesis of arabinoglycan
- Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
Resistance:
- Overexpression of emb gene products
- Mutation in embB gene
ADRs:
*** Retrobulbar neuritis (loss of visual acuity, red-green color blindness)
Rash
Drug fever
Streptomycin MOA, Resistance, ADRs
MOA: irreversible inhibitor of protein synthesis
- Binds S12 ribosomal protein of 30S subunit
Resistance:
- Mutations in rpsL or rrs gene which alter binding site
ADRs:
- Ototoxicity (vertigo and hearing loss)
- Nephrotoxicity
- Relatively contraindicated in pregnancy (newborn deafness)
Antimycobacterial Drugs ADRs
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
Ocular Toxicity
- May be due to EMB
Rash
- All agents may cause rash
- Minor pruritic rashes – antihistamines + continue drug therapy
- Petechial rash + thrombocytopenia – discontinue rifampin
Clinical Presentation of TB
Signs/Symptoms: Weight loss Fatigue Productive cough Fever Night sweats Frank hemoptysis
Chest Radiograph:
Patchy or nodular infiltrates
Cavitation
TB treatment 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)
TB treatment 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 practice
Directly Observed Therapy (DOT)
Compared to self-administered therapy (SAT):
- Improved treatment success (# cured + # completing treatment)
- Increased sputum smear conversion
Recommended for those:
- With drug-resistant infections
- Receiving intermittent regimens
- With HIV
- And children
Combination Drug Therapy
Drug resistant mutants – 1 bacillus in 10^6
Asymptomatic patients – bacillary load of 10^3
Cavitary pulmonary TB – bacillary load > 10^8
Resistance readily selected out if single drug used
Combination therapy, drug resistance – 1 bacillus in 10^12
Rates of resistance additive functions of individual rates
Example: only 1 in 10^13 organisms would be naturally resistant to both isoniazid (1 in 10^6) and rifampin (1 in 10^7)
2+ active agents should always be used for active TB to prevent resistance
Most active anti-TB drugs = INH and RIF
Combination (x9 months) cures 95-98% of susceptible TB cases
Regimens without a rifamycin are less effective
Adding PZA for first 2 months allows for 6 months total duration
Once susceptibility known, discontinue ethambutol from the 4 drug regimen
Latent Tuberculosis Infection (LTBI)
Lifetime risk of active disease reduced from 10% to 1% with treatment
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
Active Disease treatment
Drug susceptibility on initial isolate for all patients with active TB
Standard of therapy includes:
Initial phase – 2 months
Continuation phase – 4 or 7 months
Patient monitoring:
Adverse reactions
Adherence
Response to treatment
Initial Phase:
of active disease treatment
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
Continuation phase of active disease treatment
Two factors which increase risk of treatment failure –
- Cavitary disease at presentation
- Positive sputum culture at 2 months
0-1 risk factor: INH + RIF x 4 months (6 months total)
2 risk factors: continuation phase x 7 months (9 months total)
Drug-Resistant Active TB
Drug-Resistant TB
- Isolate resistant to one of 1st line agents (INH, RIF, PZA, EMB, or streptomycin)
Multidrug-Resistant TB (MDR-TB)
- Isolate resistant to at least INH and RIF
Extensively Drug-Resistant TB (XDR-TB)
- Isolate resistant to at least INH, RIF, and FQ, + either AGs or capreomycin, or both
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
Drug-Resistant Active TB medication groups
Group 1
1st line oral drugs (use all possible)
INH, RIF, EMB, PZA
Group 2
Fluoroquinolones (use one)
Levofloxacin, moxifloxacin, ofloxacin
Group 3
Injectable agents (use one)
Capreomycin, kanamycin, amikacin, streptomycin
Group 4
Less effective, 2nd line drugs (use all possible if necessary)
Ethionamide, cycloserine, aminosalicylic acid
Group 5
Less effective or sparse data (use all necessary if < 4 from other groups)
Bedaquiline, clofazimine, amoxicillin/clavulanate, linezolid, imipenem/cilastatin, clarithromycin
HIV infection with TB- treatment
LTBI
INH x9 months preferred
Alternative: INH + rifapentine weekly x12 weeks, if not on ART
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%
Immunomodulating Drugs
TNF-α inhibitors increase risk of LTBI–> active disease
Screen patients prior to initiation of TNFα inhibitors
LTBI should be treated prior to initiating immunomodulating drugs
Pregnancy and 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 –> limited safety data, not recommended in US
