antiTB Flashcards
what are the characteristics of mycobacterium tuberculosis
slow growing, acid fast bacilli, aerobic
what is tuberculosis caused by
caused by mycobacterium tuberculosis
which group of patients are more susceptible to have active TB
immunocompromised, elderly, HIV positive
is it active TB during initial infection
no it stays dormant and has no symptoms (latent TB) and risk of progression to active TB highest in first two years after initial infection
what are the measures taken to combat TB in singapore
promotion of directly observed therapy (DOT), national treatment surveillance registry to monitor treatment progress and outcome for all TB patients, contact investigations
how do you clinically diagnose TB
- history of close contact
- risk factors
- clinical presentation
- physical exam findings using sputum
- chest x ray findings
what are the risk factors of TB
immune status (HIV, DM), living conditions, nutritional status, age
what is the clinical presentation of TB
fever, night sweats, hemoptysis, weight loss
what is the test done using sputum for diagnosis of TB
ziehl neelson stain for acid fast bacilli
what are the principles of TB treatment
different subpopulations have different metabolic activity for active TB, treatment should be prolonged to prevent transmission and ensure eradication else may cause relapse, avoid monotherapy to prevent drug resistance
what are the MOH guidelines for TB treatment
- assess baseline liver enzymes before initiating
- if to start of ethambutol, assess patient’s visual acuity and colour vision
- document patient’s weight at every visit and adjust dose accordingly
- patients with high risk of drug induced hepatitis must be closely monitored
- 6 month regimen
what does the 6 month regimen comprise of
2months intensive phase of daily rifampicin, isoniazid, pyrazinamide, ethambutol
4months continuous phase of daily or 3x/w rifampicin and isoniazid
what is the moa of rifampicin
inhibit gene transcription by blocking DNA dependent RNA polymerase and prevents mRNA and protein synthesis thus leading to cell death
what is the moa of isoniazid
prodrug that is activated by catalase peroxidase to form oxygen derived free radicals that inhibit formation of mycolic acids of bacterial cell wall thus leading to DNA damage and cell death
what is the moa of pyrazinamide
prodrug which is converted into its active form pyrazinoic acid by pyrazinamidase microbial enzyme which enters bacilli passively -> rich high conc in bacterial cytoplasm where there is accumulation of pyrazinoic acid that decreases intracellular pH to levels that inactivate critical pathways necessary for bacterial survival
what is the moa of ethambutol
inhibit arabinosyltransferase enzyme encoded by embB gene and interfere with polymerisation of arabinose to arabinogalactan which is principal polysaccharide of mycobacterium cell wall thus affect integrity and facilitate entry of lipophilic abx like rifampicin and levofloxacin
what class is streptomycin
aminoglycosides
what is the moa of aminoglycosides
bind to 30S ribosomal subunit -> distorts structure of ribosomes -> block formation of initiation complex -> cause misreading of codons as wrong amino acyl tRNAs bind to A site without matching the codon present in mRNA at that position -> translocation inhibited
which phases of bacilli does rifampicin kill
metabolically active and bacilli in stationary phase
what are the indications of rifampicin
active TB in combi with other antimycobacterials, latent TB, leprosy against mycobacterium leprae
what are the resistance of mechanisms to rifampicin
mutations in gene which encodes RNA polymerase beta chain
PK characteristics of rifampicin
oral, best taken on empty stomach
cns conc 10-20%, penetration increased in meningitis
hepatically metabolised 65% excreted in bile
no renal dose adjustments as not renally cleared, monitor liver function due to hepatotoxicity
what are the adverse effects of rifampicin
- cutaneous syndrome that is self limiting and can be managed by antihistamine therapy, can continue treatment (flushing and/or pruritis, redness and watering of eyes)
- flu like syndrome (fever, chills, malaise, headache and bone pain)
- respiratory syndrome (sob)
- thrombocytopenia, hemolytic anemia and acute renal failure (rare)
- orange discolouration of bodily fluids (tears, sweat, urine)
- hepatitis due to hepatotoxicity (but less than isoniazid and pyrazinamide)
- GI symptoms like N, abdominal discomfort, anorexia - administer after light meal or before bedtime
what is the pregnancy category of rifampicin
category C
what should be given to pregnant mothers taking rifampicin and why
vitamin K to prevent postpartum hemorrhage
what should be monitored if give rifampicin to breastfeeding mothers
infant for jaundice
what is the c/i for rifampicin
history of hypersensitivity to rifampicins
what are the drug interactions for rifampicin
rifampicin can induce certain cyp450 which increases metabolism of drugs that are partially or completely metabolised by cyp450 like warfarin, corticosteroids, hormonal contraceptives, HIV protease inhibitors
what type of bacilli does isoniazid have effect on
bactericidal effect on rapidly growing bacilli, limited effect on slow growing and intermediate growing bacilli
what are the indications of isoniazid
- active TB in combi with other antimycobacterials
- latent TB
- prophylaxis
what are the mechanisms of resistance for isoniazid
- mutations to catalase peroxidase enzyme
- mutations to regulatory genes involved in mycolic acid synthesis
PK characteristics of isoniazid
oral, best taken on empty stomach
half life 1hr for fast phenotype, 2-5h for slow phenotype, good csf penetration
metabolised through acetylation in liver by N-acetyltransferase (acetylation rate related to genetic polymorphism)
inactive metabolites excreted by kidney
monitor liver function, no renal dose adjustments as not renal cleared
what are the adverse effects of isoniazid
- peripheral neuropathy (pricking pain, paresthesia, burning sensation in hands and feet)
- hepatitis due to hepatotoxicity (risk increases with age, ROH use, concomitant use of other nephrotoxic agents)
- rarely - convulsions, toxic psychosis, hematologic reactions, lupus like syndrome, hypersensitivity
what should be given if pregnant take isoniazid
pyridoxine
what should be given if breastfeeding take isoniazid
child and mother take pyridoxine
what pregnancy category is isoniazid
category c
what should be monitored if breastfeeding take isoniazid
monitor baby for jaundice
what are the metabolic pathways of isoniazid
N-acetyltransferase 2 pathway (NAT2): produces acetyl-hydrazine
amidase pathway: produces hydrazine
is isoniazid and its metabolites hepatotoxic
isoniazid and acetyl-hydrazine is not hepatotoxic, hydrazine is hepatotoxic
what are the food interactions of isoniazid
carbs can reduce absorption by 57%, avoid tyrosine and histamine rich foods as they block monoamine oxidase enzymes and histaminase which can result in flushing and headache
what are the drug interactions of isoniazid
cyp450 inhbitor thus can increase plasma conc of anticonvulsants and anticoagulants, separate antacids and isoniazid by 2hrs as antacids increase gastric pH which can delay absorption of isoniazid
what is pyridoxine
naturally occurring B6 that is converted into active form pyridoxal phosphate after being absorbed from GI tract and the cofactor is involved in many metabolic processes
what is the role of pyridoxine
prevent pyridoxine deficiency which is essential for cns function and can prevent peripheral neuropathy
what can taking pyridoxine with isoniazid help with
prevent peripheral neuropathy
what are the similarities between pyrazinamide and isoniazid
structurally similar
does the similarities of pyrazinamide and isoniazid cause cross resistance
no
what type of mycobacterial is pyrazinamide most effective for
resistant mycobacterium that are responsible for relapse
what benefit does pyrazinamide have
reduces therapy of RIP to 6 months
what are the indications for pyrazinamide
active TB in combi with other antimycobacterials
what are the mechanisms of resistance to pyrazinamide
mutations in the gene encoding for pyrazinamidase
PK characteristics of pyrazinamide
oral, well absorbed
widely distributed, high cns penetration
metabolite eliminated by kidney, renal dose adjustments needed as metabolites can accumulate if kidney failure
what are the adverse effects of pyrazinamide
GI (N,V), photosensitivity, hepatotoxicity, hyperuricemia and arthralgia, exanthema (widespread rash) and pruritus
what is the pregnancy category of pyrazinamide and can it be used in preganacy
category C, safe to use
can pyrazinamide be used in breastfeeding, what should be monitored
compatible, monitor for jaundice
why does pyrazinamide cause hyperuricemia and arthralgia
active form pyrazinoic acid inhibits renal tubular secretion of uric acid which results in gout like symptoms
what are the c/i for pyrazinamide
generally avoid in hepatic failure else, closely monitor and go for labs frequently
what type of effect and what kind of bacteria is ethambutol effective for
bacteriostatic, rapidly growing bacilli
what type of effect and what kind of bacteria is ethambutol effective for
bacteriostatic, rapidly growing bacilli
what are the indications for ethambutol
active TB in combi with other antimycobacterials
what are the mechanisms of resistance to ethambutol
mutations in embB gene
PK characteristics of ethambutol
oral, 75-80% absorbed
does not pass through healthy meninges, can reach therapeutic levels in meningitis
25% metabolised in liver, 25% excreted unchanged in feces, 50% unchanged in urine
renal dose adjustments required in kidney failure as ethambutol and metabolites can accumulate but can use full dose if liver failure
what are the adverse effects of ethambutol
- visual toxicity (decrease in visual acuity, red green colour blindness, blurring, central scotoma)
- hyperuricemia due to reduction in uric acid excretion by kidney (P>E)
what are the factors that increases risk of central scotoma effects by ethambutol
elderly, kidney failure, treatment >2m
what pregnancy category is ethambutol and can it be used
category C, safe to use
can ethambutol be used when breastfeeding
yes
what are the drug interactions of ethambutol
separate by 2h with antacids
what are the indications for streptomycin
first line antiTB drug in SG, can be used to replace ethambutol in intensive phase
PK characteristics of streptomycin
IM, poor csf penetration, excreted unchanged in urine
what are the adverse effects of streptomycin
ototoxicity (vertigo and ataxia, tinnitus, hearing loss), nephrotoxicity, neurotoxicity
what factors increases risk of ototoxicity if take streptomycin
age >40 years, risk incr with dose, can cause fetal ototoxicity
what circumstances are drug resistant TB present in
patients who were previously treated, fail treatment, known contacts of patients with MDR TB, from countries with high prevalence like India, Philippines, South Africa, Russia
what constitutes as a cure for TB
initially culture pos patient demonstrating neg sputum smear or culture in the last month of treatment and at least one prev ocassion
what constitutes as a treatment failure for TB
pos sputum on or after 5m of treatment
what is a good marker for relapse of TB
nonconversion of sputum culture at 2m
what must medical professionals do in relation to TB cases
must report both new or relapsed TB incl suspected cases and their treatment outcomes to MOH
