Tuberculosis: treatment and prevention Flashcards
what are the goals of Goals of TB treatment
Cure the patient of TB
* Prevent transmission of TB to
others
* Prevent the development of
acquired resistance
* Prevent relapse
* Prevent death from TB or its
complications
Principles of TB treatment
Combination Therapy
* Usually, combination tablet
* Intensive and continuation
phase
Period
* Period varies until TB
bacteria are eradicated in
different places
Adherence
* Counselling sessions
Drugs used as treatment for TB
isoniazid
ethambutol
pyrazinamide
Rifampicin
First line TB treatment: mechanisms of action of the drugs
Isoniazid (INH /H)
Inhibits synthesis of the mycolic acid layer of the mycobacterial cell wall
Ethambutol (E)
Inhibits synthesis of the arabinogalactan
layer of the mycobacterial cell wall
Pyrazinamide (PZA / Z)
Converted to an acid in the cytoplasm of the mycobacterium, acidify the intracellular environment and
compromise the integrity of the cell
membrane (only effective in dormant mycobacteria)
Rifampicin (Rif / R)
Inhibits mycobacterial RNA synthesis by binding to and inhibiting the
site and stage of infection: Rifampicin
Bactericidal for intra and extracellular bacteria.
Sterilising activity
Drug used foe excellent early bactericidal activity
Isoniazid
site and stage of infection: pyrazinamide
Mycobactericidal for intracellular mycobacteria in an acidic
medium.
Most useful during intensive phase
Ethambutol
Bacteriostatic (bactericidal at hight doses)
: monitoring safety of TB treatment
Hepatotoxicity monitoring (rifampicin, isoniazid, pyrazinamide).
Monitor liver function: DILI (drug-induced liver injury) * High risk patients: chronic infectious hepatitis, pre-existing liver disease, MDR
TB patients, high levels of alcohol consumption, other hepatotoxic drugs,
HIV+, females and elderly
* Screening for hepatotoxicity: new onset abdominal pain, nausea & vomiting,
jaundice / dark urine
* Check bilirubin and transaminases (5x the upper limit / 3x the upper limit
with jaundice
Management of adverse effect of Rifampicin
Side-effect
CI: oral contraceptives
Nausea, GI disturbances
Discoloration of body fluids
(tears, saliva, urine, faeces) orange
/ red
Enzyme induction
take with FOOD
management of adverse effect of Isoniazid
Adverse: Peripheral neuropathy (burning /
pins & needles in feet & legs)
supple with pyridoxine
management of adverse effect of Ethambutol
Optic neuritis
Vision check-ups
management of adverse effect of Pyrazinamide
joint pain (gout), hepatotoxic.
Pharmacokinetics: Rifampicin
- Metabolism in the liver – cause
autoinduction and potent
enzyme inducer * Elimination: primarily biliaryfaecal route - Hepatotoxic
- Drug-interactions with drugs
metabolised in the liver * Oral contraceptives & progestin
implants (replace with injectable
contraceptives) * Orange/red/brown pigmentation
of body fluid
Pharmacokinetics Isoniazid
- Distribution: wide including the
CSF - Metabolism in the liver via
acetylation (slow acetylators at
greater risk of neurotoxicity) * Inactive metabolites excreted in
the urine - Hepatotoxic
- Neurotoxic (peripheral
neuropathy, seizures, psychosis,
ataxia & optic neuritis) reversed
by pyridoxine (B6) * Drug-interactions with drugs
metabolised in the liver (weak
enzyme inhibitor) * Caution in patients with ep
Ethambutol
- Distribution: wide not in CSF
- Metabolism in the liver up to
15% - Mainly unchanged in the urine
cautions of Ethambutol
Cautions: renal failure, in
children under 8 years (visual
symptoms difficult to assess),
hyperuricaemia
* Ocular toxicity – patient selfmonitoring (reading fine print),
monitor: colour discrimination
and visual field
Pharmacokinetics: Pyrazinamide
- Distribution: wide including the
CSF - Dose-related hepatotoxicity
- Hyperuricaemia (caused by
decreased uric acid clearance)
associated with arthralgia (may
precipitate gout
The wanted. outcomes of TB
- Prevent TB transmission
- Cure with minimal problems
- Cure with chronic lung disease
The unwanted outcomes of Tb
Transmission of TB
* MDR / XDR
* Death
MDR-TB
is a form of tuberculosis that is resistant to at least two of the most potent first-line anti-TB drugs, isoniazid and rifampicin. It poses a significant challenge to tuberculosis control efforts worldwide due to its complexity, prolonged treatment duration, increased costs, and higher rates of treatment failure and mortality compared to drug-susceptible TB.
Drug-resistant TB: categories
Mono-resistant TB
* Poly-resistant TB
* MDR-TB
* Rifampicin resistant-TB (RR-TB)
* Resistance to at least rifampicin
* Extensively drug-resistant TB (XDR-TB)
* Pre-XDR-T
Multidrug resistant
MDR In vitro resistance to:
* Rifampicin
* Isoniazid
* With or without resistance to other
anti-TB drugs.
XDR (extensively DR)
- MDR TB
- +
- In vitro resistance to: * Any fluoroquinolone * AND
- Any injectable drug
- Extremely difficult and expensive to treat with a high mortality (90%) in HIV co-infected
Isoniazid resistance is caused by
- inhA mutation and
- katG mutation
Drug-resistant TB treatment regimens
Short regimen
Pre -2024 – old regimen being phased out:
Short course: * At least 6 drugs used for 9 months. for adults, pregnant and kids> than 6 yrs
2024 – new regimen being phased in: * BPaL-L: * At least 3 drugs used for 6 month. for 6 months
Long regimen
Long regimen
* 18 months
* Complicated EPTB / extensive
disease on CXR
* Children < 6 years
* Hx of previous treatment with 2nd
line drugs for more than 1 month
* Contact with XDR / Pre-XDR
* Both INH mutations
The 6-month BPaL-L regimen;
short course
Bedaquiline,
* Pretomanid,
* Linezolid (600 mg)
* With or without levofloxacin (if sensitive)
core drugs for long regime
- Bedaquiline, * Linezolid
- Levofloxacin (substitute if fluoroquinolone resistance) * Clofazimine
- Terizidone
Co-administer pyridoxine to
prevent peripheral neuropathy due to terizidone: dose for adult and children
50 mg for adults
25 mg for children
Bedaquilline
do not use for kids for less than 6 yrs
since Bedaquiline is used in kids greater than 6 yrs it is substituted by what drugs
- Delamanid (3 to 6 years) * Para-aminosalicylic acid (less than (<)3 years)
The mechanism of action of bedaquiline
inhibit mycobacterium ATP synthase
metabolised by CYP3A4 need LFT monitoring (ALT, AST, bili) * DI: CYP3A4 inhibitors / inducers, hepatotoxic drugs
* Major adverse effects: QT prolongation (ECG monitoring – stop if
>500ms) * DI: fluoroquinolones, macrolides, clofazimine, disease
The drug that inhibits peptidoglycan synthesis and is widely distributed including CSF
Terizidone
Major adverse effects of Terizidone
Peripheral neuropathy (treat with pyridoxine or amitriptyline) * DI: isoniazid
* Seizures, anxiety, depression, psychosis
* CI: psychiatric disorders / symptom
a weak enzyme inducer drug
isoniazid
which drug causes renal failure and hyperuricemia in children less than 8 years ?
Ethambutol
remember it is not given to kids < 8 for TB treatment, affects the optic nerve, not metabolized by the liver that much. and it is bacteriostatic but can kill at high doses.
excreted in urine
inhibit synthesis of arabinogalactan
drug that is dose-related hepatotoxicity and widely distributed in the CFS.
Pyrazinamide
drug that is bactericidal in an acidic medium.
Pyrazinamide.
extremely difficult and expensive to treat and has a high motility rate in HIV infected patients.
extra Drug-resistant.
individualized long regimen designed according to who grouping?
if Rifampicin-resistant meningitis
if resistant to Bedaquiline, linezolid, pretomanid and cfs
Bedaquiline is safe to use in ?
above 6 years
inhibit peptidoglycan synthesis and is widely distributed including CFS
Terizidone
Major adverse effects: Terizidone
Peripheral neuropathy (treat with pyridoxine or amitriptyline) * DI: isoniazid
* Seizures, anxiety, depression, psychosis
* CI: psychiatric disorders / symptoms
adverse effect of clofazimine
Adverse effects: common - red/brown pigmentation of conjunctiva and skin and body fluids
* QT prolongation
* DI: fluoroquinolones, macrolides, bedaquiline
* Monitor hepatic function
* Counselling: take with food to diminish GI upset
- Accumulate in tissues: fat, skin, liver, kidneys and reticulo-endothelial cells – cause red-brown pigmentation of conjunctiva and skin; may impart red colour to urine,
sweat, tears, sputum - Eliminated in bile and faeces
clofazimine
used in children between 3-6 years. substutite of bedaquiline. and has adverse effect of insomia, hallucination, night terrors.
delamanid
Pretomanid
MOA: inhibit bacterial cell wall mycolic acid biosynthesis
* Administered with bedaquiline and linezolid to treat resistant forms
of pulmonary TB
* Major adverse effects: Peripheral neuropathy, acne, anaemia,
SYMPTOMS FOR SCREEN
Cough (any duration) * Fever * Unexplained weight loss
* Night sweats
* History of previous TB
* Adherence to ART
