Tuberculosis - Treatment (III) Flashcards
4 first line drugs for TB
Standard Regimen
Isoniazid (H) -300mg
Rifampicin (R) - 600mg
Ethambutol (E) - 900mg
Pyrazinamide (Z) - 1.5g
for 60kg patient
Standard Rx: 2HREZ/ 4HR
2 months 4 drugs + 4 months 2 drugs
Location for TB drug admin?
Supervised daily treatment at chest clinics under DoH
4 common, mild adverse reactions to standard TB regimen
GI: discomfort, low appetite (Pyrazinamide)
Skin reaction/ allergy
Vestibular (Streptomycin)
Liver derangement
Serious adverse reaction special for ethambutol?
- 3 symptoms
- Management?
ETHAMBUTOL OPTIC NEUROPATHY (metal chelating effect)
Bilateral progressive painless visual blurring
Changed color vision
impair central vision
- Stop ethambutol
- Optic neuropathy generally reversible and low dose is advised
Serious Hepatitis symptoms caused by which TB drug?
Symptoms?
Rifampicin
Abdominal pain
Brown urine **
Fever, fatigue, flu-like symptoms
Nausea and vomiting
2 Serious adverse reactions specific for isoniazid?
Nervous system damage: Dizziness, tingling/ numbness at mouth
Peripheral pneuropathy
2 Serious adverse reactions specific for pyrazinamide
Stomach upset
Gout*: abonormal uric levels, joint aches
3 Serious adverse reactions specific for rifampicin
Bleeding problems: easy bruising, slow clot
Discoloration of body fluids: orange urine, sweat or tears
Drug interactions: many drugs
Management of GI upset from TB drugs?
- Exclude hepatitis by blood test
- Take drugs with food, take at bedtime
- No split doses, use single daily dose regimen
- Antiemetics (but not antacids)
2 forms of fixed dose combination of TB drugs?
Drawback?
Rifater: H, R, Z
Rifinah: H, R
- Cannot modify dose e.g. for patient with renal impairment, cannot modify dose
Management of non-petechial rash from TB drugs
mild rash? severe rash?
- Exclude other causes (e.g. viral infections)
- Mild rash = antihistamine or topical steroid
- Moderate to severe rash = stop TB drugs, give anti-histamine, systemic steroid
- Watch for progression and mucosal involvement, consult dermatologist
List 5 emergency complications of TB drugs
Hepatitis (HRZ)
Retrobulbar neuritis (E)
Thrombocytopenia (R)
Acute renal failure (R)
SJS
Hepatotoxicity from TB drugs.
- Host risk factors?
- When to stop TB drugs?
- Management
Risk factors: alcoholics, Chronic viral hepatitis
Threshold: ALT 3x OR Bilirubin 2x upper limit of normal
Stop treatment, reintroduce regimen with less hepatotoxicity (e.g. streptomycin, amikacin, ethambutol …etc)
ALT levels continue to rise after stopping TB drugs after clinical signs of hepatitis.
Normal or Abnormal?
Normal
ALT takes 1-2 weeks to reach peak levels then return to normal in drug-induced hepatitis
4 risk factors for hepatotoxicity from TB drugs?
Old
Low BMI
Malnutrition
Pre-existing liver diseases: alcoholic liver disease, chronic viral hepatitis
ALT and ALP levels fluctuates around normal levels after starting TB drugs.
Should TB drugs be stopped?
No
ALT and ALP fluctuation is normal
Severe end-stage drug-induced hepatotoxicity.
- How to assess?
- Treatment?
- Prevention?
Serum bilirubin 2X + Transaminase increase
Both increase at the same time = severe hepatotoxicity.
(Hepatotoxicity = only transaminase rise)
End- stage liver transplant
Stopping TB drugs earlier = better prognosis
Recommended dosage for ethambutol?
- 15mg/kg/day (normal kidney)
- 7.5mg/kg/day (impaired kidney, GFR <30mL/min)
Management of ethambutol optic toxicity
- Maintain low dose at 15mg/kg/day
- Drug-susceptibility test for ethambutol > stop if positive
- Lower dose for renal impairment
- Warn all patients to report change in vision ASAP
- Check vision of at-risk patients monthly
Which TB drug causes acute kidney injury?
- Mechanism?
- Pathologies?
Rifampicin
Type II or III hypersensitivity reaction: rifampicin antigens + anti-rifampicin antibody complexes deposit in renal vessels, glomerular, interstitial space
Acute interstitial nephritis
Acute tubular necrosis
Which TB drug causes thrombocytopenia?
Rifampicin
Antiplatelet antibodies generated»_space; low platelet
Which TB drug causes peripheral neuropathy?
- Host risk factors?
- Prophylaxis?
Isoniazid
Risk factors: elderly, DM, alcoholism, slow acetylator phenotype, HIV, renal failure
Prophylaxis: Pyridoxine 10-20mg/day up to high dose 50-100mg/day
Which TB drug causes the most drug interactions?
- Mechanism? ***
Rifampicin
Powerful inducer of CYP450 enzyme system > increase metabolism/ catabolism of many drugs > decrease drug effectiveness
Give examples of drugs that interact with rifampicin (6 main classes)
Anticoagulants: Warfarin HIV: PI and NNRTI Oral hypoglycemic drugs (sulphonylureas) Anticonvulsants: phenytoin Contraceptives Immunosuppressants
Special management for young, female patients taking rifampicin in TB regimen?
Stop oral contraceptives, change to other contraceptive methods
Effect of rifampicin on warfarin and corticosteroids?
Need much higher dose of warfarin and corticosteroids (e.g. for Addison disease) than normal
Treatment for HIV patients with TB infection?
Which drugs should not be used?
Which HIV drugs to use?
Normal HIV patient: TB treatment first + ART treatment within 8 weeks
Severely immunocompromised HIV patient: TB treatment first + ART treatment within 2 weeks
Do not use protease inhibitor (PI) or NNRTI
Use Efavirenz-based or Raltegravir-based regimen + 2 NRTIs
If a patient is on long-term therapy with drugs that interact with Rifampicin, should rifampicin be substituted in treating TB infection?
No
Rifampicin should be kept. Should not be substituted because of drug interactions.
Isoniazid drug interaction:
- Mechanism?
- Drugs interacted?
- Effect with Rifampicin?
Isoniazid = potent inhibitor of CYP isozymes»_space; Increase concentration of some drugs to toxic levels
Examples: Increase benzodiazepine levels (metabolized by oxidation)
Rifampicin induce CYP, Isoniazid inhibit CYP»_space; overall effect balances each other
Fluoroquinolone drug interaction:
- Mechanism?
- Drugs interacted?
- Management if taking interactive drugs and fluoroquinolone?
Interfere GI absorption of antacids, sucralfate, metal cations»_space; Low systemic levels
Take interacting drugs at least 2 hours before fluoroquinolone
Most effective method in control of TB?
Direct Observed Therapy
Take every dose under supervision = complete whole course, lower treatment failure, drug resistance, disease spread
Risk factors for TB therapy default
Smoking History of default Poor initial adherence pattern Strong side effects from treatment Hospitalization
3 factors that determine probability of TB transmission
- Infectiousness of person with TB (e.g. Positive culture, sputum smear, CXR, symptoms…etc)
- Duration and frequency of exposure (e.g. close contacts)
- Environment of exposure (e.g. crowded, poorly ventilated)
5 aims of TB contact tracing.
- Find source of infection
- Find contacts with active TB, isolate
- Find uninfected close contacts for BCG vaccine
- Educate contacts about TB, seek medical advice early with symptom
- Find Latent TB for preventative regimen
WHO recommendation for close contact TB inestigation?
If contact has:
- sputum smear-positive pulmonary TB
- PLHIV
- is a Child under 5
Define Mono- , Rifampicin- , and Polyresistance TB
Mono-resistant: 1 first line drug only
Rifampicin resistant
Polyresistance: More than 1 first line drug other than Isoniazid and rifampicin
(Isoniazid and rifampicin = MDR-TB, not polyresistant)
Define MDR-TB and XDR -TB
MDR-TB = Resisatnt to at least both Isoniazid and Rifampicin
XDR - TB = Resistant to any fluoroquinolone + At least one of 3 injectables (Capreomycin, Kanamycin, Amikacin) + MDR
Drawback to conventional TB drug susceptibility testing?
Slow: microscopy, culture from isolated clinical specimen for susceptibility testing
- Time for resistance amplification
- Wrong treatment for patient
- Resistant strains keep spreading
Name 2 fast TB drug susceptibility test?
Xpert MTB/ RIF Ultra
Line Probe Assays - 1st line = rifampicin and isoniazid resistance; 2nd line = fluoroquinolone and injectable resistance
Treatment of MDR-TB (5 drugs)
At least:
- Pyrazinamide
- Fluoroquinolone
- Parenteral agent (injectables)
- Ethionamide
- Cycloserine or PAS
Treatment of XDR-TB
MDR regimen + FQ + bedaquiline or linezolid
List 2 new Add-on agents/ Group D TB drugs
Are these commonly used?
Bedaquiline (diarylquinoline) = not really used (long QT interval)
Delamanid (nitromidazopyran, inhibit mycolic acid biosynthesis) = not used
Adverse effects of Bedaquiline
QT prolong
Hepatotoxicity
CYP3A4 drug interaction
Long half life
Linezolid.
Used or not in MDR-TB?
Adverse effects?
No
Peripheral neuropathy
Bone marrow suppression
Current recommendation of MDR-TB: Class A and Class B?
Class A: (use 3)
- Levofloxacin
- Bedaquiline
- Linezolid
Class B: (choose 1)
- Clofazimine
- Cycloserine or terizodone
Isoniazid resistant TB treatment
Rifampicin + ethambutol + Pyrazinamide + Levofloxacin
6 months
Effects of BCG vaccine?
Efficacy globally?
Effects on primary infections or latent TB?
Protective against meningitis and disseminated TB in children
Slow decline globally
Does not prevent primary infection, prevent reactivation of latent pulmonary infection