Tuberculosis 3: TB Drugs Flashcards
1st line drugs for drug susceptible TB
- Isoniazid (H): 300mg
- Rifampicin (R): 600mg
- Ethambutol (E): 900mg
- Pyrazinamide (Z): 1500mg
(for 60kg patients)
Standard regimen:
- ***2 HREZ / 4HR (2 months 4 drugs —> 4 months 2 drugs)
- Supervised daily at chest clinics
ADR of TB regimen
- GI
- mild abdominal discomfort
- decrease appetite - Cutaneous reaction
- Vestibular (Streptomycin)
- Liver derangment
***Serious adverse reactions
- Hepatitis (H, R, Z)
- Retrobulbar neuritis (E)
- Thrombocytopenia (R)
- Acute renal failure (R)
- SJS
***SE of drugs
Isoniazid (H):
- ***Peripheral neuropathy (pyridoxine B6)
- Nervous system damage (tingling / numbness around mouth)
- Hepatitis
Rifampicin (R):
- **Red-orange discolouration of secretions
- **Enzyme inducer
- ***Easy bruising / Slow blood clotting
- Hepatitis
- Acute renal failure
Ethambutol (E)
- ***Retrobulbar neuritis (not recommended under 5)
—> blurred vision / changed colour vision
Pyrazinamide (Z):
- **Hepatotoxicity
- GI symptoms
- Hepatitis
- **Gout
Streptomycin:
- ***Affect hearing (Tinnitus)
- Giddiness
- Cutaneous hypersensitivity
GI upset: Guideline
- Exclude hepatitis with blood tests
- ALT <3 times upper limit
- Total Bilirubin <2 times upper limit
(ALT (more specific to liver), AST: Parenchymal enzyme
ALP, GGT (more specific to liver): Ductal enzyme)
- Administer drugs with food
- Anti-emetic
- ***avoid antacids (∵ ↓ absorption of Isoniazid + Rifampicin) - Daily regimens if symptoms related to bulk of medications in intermittent regimens
- Fixed dose combination may help - No split doses —> result in suboptimal drug levels —> acquired resistance
- Medication at bedtime may help (if self-administered treatment)
Non-petechial rash: Guideline
- Exclude other causes
- Mild: Symptomatic relief with **Antihistamines / **Topical steroid
- watch out for progression + mucosal involvement - Moderate - Severe: ***Suspend treatment, Antihistamine, Systemic steroid (if life-threatening)
- reintroduce drugs later with caution - Consult dermatologist if necessary
Hepatotoxicity: Guideline
- Identify underlying risk factors (e.g. alcoholics, chronic viral hepatitis)
- Withhold treatment if ALT >3 times / Total Bilirubin >2 times upper limit
- If Hepatitis suspected clinically, may ***withhold treatment until blood results available
- ***Reintroduce drugs when ALT return to normal / baseline
- If Extensive TB, earlier reintroduction may be considered when ALT on ↓ trend / clinically stable
- Non-hepatotoxic interim regimen may be considered
Risk factors for Drug-induced Hepatotoxicity
- Old patients
- Low BMI
- Malnutrition
- Pre-existing liver disease: Alcoholic liver diseases, Chronic viral hepatitis (HBV, HCV etc.)
Prognosis of Drug-induced Hepatotoxicity
- Liver function return to normal in most cases if drugs stopped early
- No specific treatment
- Hepatoprotective agent ***no use
- Complications: ***Fulminant hepatic failure (may require liver transplantation)
- Bilirubin >2 times ULN with associated transaminase rise is dangerous sign
—> Severe hepatotoxicity
—> Can lead to mortality if drug not stopped
Ocular toxicity
Ethambutol
Retrobulbar neuritis:
- Bilateral progressive **painless visual blurring
- **↓ Colour perception
- ***Central vision most commonly affected
- Usually delayed onset (months after initiation)
- Progressive (most typical) / Acute / Chronic
Prognosis:
- Generally **reversible
- Dependent on **dose + duration
Treatment:
- Therapy discontinuation (stop progression + allow recovery)
- Stop Isoniazid also 6 weeks after stopping Ethambutol if no vision improvement
Location recommendation:
- Keep 15mg/kg daily OR 30mg/kg three times weekly
- Discontinue ethambutol as soon as drug-susceptibility shows no use
- 15mg/kg three times weekly (instead of daily) if GFR < 30 ml/min
- **Warn patients to report change in vision immediately
- Check patients weights at least monthly
- Any risk factors for optic neuropathy / need to take > 8 weeks —> Check vision monthly (esp. Colour vision)
Rifampicin-induced AKI
Mechanism not well established
- Type 2 / 3 hypersensitivity reaction induced by Rifampicin Ag
—> Anti-Rifampicin Ab form immune complexes
—> deposit in renal vessels, glomerular endothelium, interstitium
Prognosis:
- Generally favourable
Thrombocytopenia
Rifampicin
Intermittent therapy > Daily therapy
Mechanism:
- Presence of Antiplatelet Ab —> Thrombocytopenia
Peripheral neuropathy
Isoniazid
- ***Dose dependent
- Uncommon at 5 mg/kg/day
- More common in elderly, DM, alcoholism, slow acetylator phenotype, HIV, renal failure
Prophylaxis:
- Pyridoxine 10-20mg daily
Treatment:
- Pyridoxine 50-100mg daily
Cutaneous adverse reaction
Spectrum of disease:
- mild maculopapular rash
- acute generalised exanthematous pustulosis
- DRESS (drug reaction with eosinophilia + systemic symptoms)
- epidermal necrolysis (SJS)
Rifampicin drug interactions
CYP450 inducer (most powerful)
- 2B6, 2C8, 2C9, 2C19, 3A4, 3A5, 3A7, 3A, 2C
—> ↑ metabolism of many drugs
—> Rifampicin Inductive effect»_space; Isoniazid Inhibitory effect
—> overall should ↓ dose of affected drugs
Drugs affected:
1. Oral hypoglycaemic drugs (***sulphonylureas)
-
**PI, NNRTI (HIV drugs)
- ART should be started in all HIV patients with TB regardless of CD4
- initiate TB treatment first —> ART asap within 8 weeks (2 weeks if very low CD4)
- Use **Efavirenz + 2 NRTI (if concurrent HIV + TB) - Warfarin
- 5-7 days after initiation —> 5-7 days after withdrawal - Phenytoin
- Oral contraceptives
- recommend female patients of reproductive age take extra contraceptive methods - Immunosuppressants (Corticosteroid, Cyclosporine, Tacrolimus)
- Addison’s disease should ↑ Corticosteroid dosage
Isoniazid drug interactions
Potent ***Inhibitor of CYP isozymes
—> ↑ conc of some drugs to toxicity level
—> Rifampicin Inductive effect»_space; Isoniazid Inhibitory effect
—> overall should ↓ dose of affected drugs
Drugs affected:
1. Phenytoin
2. Carbamazepine
3. Benzodiazepines metabolised by ***oxidation: Diazepam, Triazolam (but not those metabolised by conjugation: Oxazepam)
Levofloxacin
**Antacids containing Mg, Al, Sucralfate, Metal cations (e.g. Fe)
—> Interfere GI absorption of Levofloxacin
—> **2 hours before / after Levofloxacin
Directly Observed Therapy (DOT)
Strongly recommended by WHO, IUATLD
—> Most effective measure to control TB
Patients provided necessary support to complete whole course of treatment
- avoid treatment failure, drug resistance, spread of disease
5 components:
1. Sustained political and financial commitment
2. Diagnosis by quality ensured sputum-smear microscopy
3. Standardised short-course Anti-TB treatment under DOT
4. Regular, uninterrupted supply of high quality Anti-TB drugs
5. Standardised recording + reporting —> keep track of each patient, monitor overall programme performance
Contact tracing
- Identify source of infection
- Identify contacts who actually have active TB
- Identify uninfected contacts —> eligible for BCG vaccination
- Educate contacts about TB —> seek medical advice early in case of developing S/S of TB
- Identify contacts who have LTBI —> consider preventive Rex
Based on:
1. Infectiousness of index case
2. Degree of closeness of contact
3. Susceptibility of contact people
WHO recommendation:
Conduct for house-hold + close contacts when ***index case:
1. Sputum smear-positive pulmonary TB
2. People living with HIV (PLHIV)
3. Child < 5 age
Risk of progression:
- 5-10% of infected will develop active TB
- 10% for HIV +ve
- other medical conditions: silicosis, DM, alcoholism etc.
***Drug resistant TB
- Mono-resistance (ONE 1st line drug only)
- Rifampicin-resistance RR (Rifampicin with / without resistance to other drugs)
- Poly-resistance (>=ONE 1st line drug other than H + R)
- ***MDR (Both H + R)
- ***XDR (MDR + Any Fluoroquinolone + >=ONE of three 2nd line injectable: Capreomycin, Kanamycin, Amikacin)
Development of resistance
Spontaneous mutation
—> Selection (∵ inadequate / improper treatment)
—> Transmission
***Never add a single drug to failing regimen (要加就要加幾隻 —> 確保殺曬全部菌)
Conventional methods for drug susceptibility testing
Isolation of mycobacteria from specimen
—> Identification of mycobacterium TB complex
—> In vitro testing of strain susceptibility to Anti-TB drugs
Slow + Cumbersome
- Patients may be inappropriately treated during this time
- Drug resistant strains may continue to spread
- Amplification of resistance may occur
Molecular drug resistance test
Detect major gene mutations associated with resistance
- Xpert MTB/RIF
- Ultra
- Line probe assays (LPA)
- 1st line LPAs: test for resistance to H + R
- 2nd line LPAs: test for resistance for Fluoroquinolone, Injectable
Treatment of Drug-resistant TB
Group 1: 1st line oral agents (HREZ)
Group 2: Injectable (Kanamycin, Amikacin, Capreomycin, Streptomycin)
Group 3: Levofloxacin, Moxifloxacin
Group 4: Cycloserine, Para-aminosalicylic acid (PAS)
Group 5: Clofazimine, Linezolid, Augmentin
Linezolid
- Treatment of serious infection by ***Gram +ve bacteria
- demonstrated in vitro activity against M TB
Problems:
1. Short-term use: Unlikely to achieve stable cure
2. Long-term use: Anaemia, Thrombocytopenia, Peripheral / Optic neuropathy
—> Optimal dosing schedule remains unclear
—> Adverse events can be significantly ↓ by ↓ dosage
Bedaquiline
- Diarylquinoline
- Inhibits mycobacterial ***ATP synthase —> interfere with bacterial energy metabolism
- 1st novel drug conditionally approved for MDR-TB
- NO cross-resistance with other drugs
Problems:
1. QT prolongation: other drugs (e.g. Fluoroquinolone, Clofazimine, Delamanid, Macrolide)
2. Hepatotoxicity: ↑ ALT
3. CYP3A4 metabolism —> drug interaction
4. Extremely long t1/2
Delamanid
- Nitroimidazopyran (derivative of Metronidazole)
- Inhibit Mycolic acid biosynthesis
MDR-TB treatment
Outdated:
Group A: Fluoroquinolone
Group B: 2nd line injectable
Group C: Other core 2nd line agents (e.g Linezolid, Clofazimine)
Group D: Add-on agents
- Bedaquiline
- Delamanid
Treatment (5 total drugs):
- Pyrazinamide
- 1 from group A
- 1 from group B
- >=2 from group C
(Add-on agent to bring to 5 total drugs if others cannot)
Newer recommendation:
Group A: Levofloxacin / Moxifloxacin + Bedaquiline + Linezolid
Group B: Add
- Clofazimine
and/or
- Cycloserine/Terizidone
Group C: Add to complete regimen or when Group A, B cannot be used
- Ethambutol
- Pyrazinamide
- Delamanid
- Amikacin / Streptomycin
- Ethionamide / Prothionamide
- Para-aminosalicylic acid
- Imipenem-cilastatin / Meropenem
Shorter MDR-TB regimen
4-6 months:
- Kanamycin
- Moxifloxacin
- Prothionamide
- Clofazimine
- Pyrazinamide
- High dose Isoniazid
- Ethambutol
Then
5 months:
- Moxifloxacin
- Clofazimine
- Pyrazinamide
- Ethambutol
Isoniazid resistant TB
Treatment (RLEZ regimen):
- R
- E
- Z
- Levofloxacin
Duration:
- 6 months
***NOT recommended to add Streptomycin / Injectables
Latent TB infection
- Isoniazid
- Isoniazid + Rifapentine
- Rifampicin
Vaccination to prevent TB
BCG vaccine: only licensed vaccine
- Slow decline in TB incidence
—> need for much more effective vaccine - Effective against **meningitis + **disseminated TB in children
- ***NOT prevent primary infection
- ***NOT prevent reactivation of latent pulmonary infection
