anti mycobacterial Flashcards
what is mycobacteria
• Slender, rod-shaped aerobic bacteria
• Slow multiplication
• Cell wall contain mycolic acids which
are long fatty acids
• Acid-fast: lipid-rich cell walls lead to
poor gram stain, no decolorized by
acidified organic solvents
• Intracellular: form slow growing
granulomatous lesions
• Mycobacterium tuberculosis causes
serious infections to
– Lungs (90% of the cases)
– Genitourinary tract
– Skeleton
– Meninges
why is the treatment of mycobacteria difficult?
• The organism grows
slowly,(requires treatment for
months to years)and it is difficult
to culture (to test for sensitivity)
• Resistance to the drugs is
common (some bacteria are
resistant to 7 drugs)
• Treatment takes 6 to 24 months
with combination of drugs
• (at least two drugs a time)
what is the first line in treatment of mycobacteria
• Isoniazid (most important)
• Rifampicin(most important)
• Ethambutol
• Pyrazinamide
• Preferred because of their:
• efficacy
• acceptable incidence of toxicity
• The multidrug regimen is continued well beyond the
disappearance of clinical disease to eradicate any
persistent organisms
what is INH
• Bactericidal to rapidly dividing mycobacteria, but
is bacteriostatic if the mycobacteria are slow-growing
• Used also as prophylaxis for all household members
and very close contacts of patients with tuberculosis
• Most potent of the antitubercular drugs
• Should be used in combination
what is the MOA for INH
• INH is a prodrug activated by a mycobacterial
catalase-peroxidase (KatG)
• Binds and inhibits the enzymes:
• acyl carrier protein reductase (InhA)
• & β-ketoacyl-ACP synthetase ( KasA)
• Which are essential for synthesis of mycolic acid, an
important component of mycobacteria cell wall
• Leading to a disruption in the bacterial cell wall
• Antibacterial spectrum:
• INH is specific for TB
• INH is particularly effective against rapidly growing
bacilli and against intracellular organism
how is resistance built against INH
• 1) Mutation or deletion of KatG (producing
mutants incapable of prodrug activation)
• 2) Varying mutations of the acyl carrier proteins,
• 3) or over expression of the target enzyme InhA.
• Cross-resistance does not occur between
isoniazid and other antitubercular drugs ( except
with ethionamide 2nd line drugs)
what are the PK of INH
• Rapid oral absorption, impaired iif taken with food, mainly high fat
foods
• Diffuses into all body fluids, cells, and caseous material (necrotic
tissue resembling cheese that is produced in TB).
• Drug levels in the cerebrospinal fluid (CSF) are about the same as
those in the serum.
• The drug readily penetrates host cells and is effective against
bacilli growing intracellularly. Infected tissue tends to retain the
drug longer.
• Elimination:
• INH undergoes N-acetylation and hydrolysis to inactive products
• INH acetylation is genetically regulated:
• Fast acetylators serum T1/2 90 minutes
• Slow acetylators serum T1/2 3-4 hours
• Chronic liver disease (as in chronic alcoholism)
decreases metabolism, and doses must be
reduced to decrease toxicity.
• Excretion is through glomerular filtration,
predominantly as metabolites.
• Slow acetylators excrete more of the parent
compound.
• Severely depressed renal function results in
accumulation of the drug, primarily in slow
acetylators.
what are the side effects of INH
• Hepatitis:
• The most serious AE, can be fatal if unrecognized and INH
treatment is continued
• Its incidence increases with:
• Age >35 yrs
• Patients who take rifampin
• Those who drink alcohol
• Peripheral neuropathy:
• Associated with paresthesia of hands and feet
• May be due to relative pyridoxine deficiency and can be avoided
by daily supplementation of pyridoxine (B6)
• CNS:
• Convulsions in patients prone to seizures
• Hypersensitivity: skin rash and fever
what drugs interact with INH
INH inhibits the metabolism of
carbamazepine and phenytoin
so potentiating their adverse
effec
what are Rifamycins?
Rifampin, rifabutin and rifapentine
• Group of structurally similar macrocyclic antibiotics, first line oral
drugs for TB
• Must always be used in combination with at least one other
antituberculosis drug to which the isolate is susceptible
Rifampin:
• has a broader antimicrobial activity than INH and can be used for
treatment of several bacterial infections
• Resistant strains rapidly emerge during monotherapy, it is never
given as a single therapy in treatment of TB
what is the MOA of rifampin
Interacts with bacterial, but not human, DNA dependent RNA
polymerase causing its inhibition blocking RNA transcription
what is the spectrum of rifampin
• Bactericidal for both intracellular and extracellular mycobacteria,
including M.tuberculosis, and atypical mycobacteria, such as M.
kansasii.
• Effective against many G+ve & G-ve organisms
• Used prophylactically for meningitis caused by meningococci or
Haemophilus influenzae.
• Most active drug, antileprosy but to delay the emergence of
resistant strains, it is usually given in combination with other
drugs.
how is resistance formed for rifampin
– Caused by a change in the affinity of the bacterial DNA-
dependent RNA polymerase for the drug ( genetic mutation)
what are the PK for rifampin
• Absorption is adequate after oral administration.
• Distribution of rifampin occurs to all body fluids and organs
• Concentrations attained in the CSF are 10-20% of blood conc
• The drug is taken up by the liver and undergoes enterohepatic
cycling.
• Rifampin can induce the hepatic CYP450 enzymes leading
numerous drug interactions.
• Rifampin undergoes autoinduction leading to a shorter elimination
T1/2 over the first 1-2 weeks of dosing
• Elimination of metabolites and the parent drug is via the bile into
the feces or via the urine
• Urine and feces, as well as other secretions have an orange-red
color; patients should be forewarned.
• Tears may permanently stain soft contact lenses
orange-red
what are the side effects for rifampin
• Rifampin is generally well tolerated
• Nausea, vomiting, and rash.
• Hepatitis and liver failure are rare.
• However, the drug should be used cautiously in patients
who are alcoholic or elderly or with chronic liver disease.
• A modest increase in occurrence of hepatic dysfunction
when co-administered with INH and pyrazinamide
• Induces cytochrome P-450, this leads to drug
interactions. Increase the metabolism of anticoagulants,
steroids in oral contraceptive, ketoconazole,HIV inhibitors, MEthadone, warfarin,propanolol……etc
