Antibiotics 4 Flashcards
What are the 4 medications used to treat tuberculosis?
- isoniazid
- rifampin
- pyrazinamide
- ethambutol
What constitutes a tuberculosis infection?
- presence of organisms which may or may not cause clinically significant disease
- only evidence of a tuberculosis infection on an X-ray would be a tiny fibrocalcific nodule at the site of infection
How is tuberculosis spread?
- acquired by person-person transmission of airborne droplets or organisms from an active case to a susceptible host
What constitutes a latent tuberculosis infection?
- positive tuberculin skin test - no disease
What constitutes an active tuberculosis infection?
- pulmonary cavitation
- mycobacteria dissemination
- presence of bacteria in sputum
- malaise, anorexia, weight loss, fever
- increased sputum, at first mucoid and later purulent
- extra pulmonary effects (liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, epididymis)
Describe mycrobacterium tuberculosis
- acid fast bacteria
- high lipid content of cell wall causes it to stain gram negative
- slow growing (divides every 16h -20 h)
- resistant to drying
- resistant to most antibiotics
- resistant to host killing
- intracellular survival
How does a person become infected with tuberculosis?
- TB is spread by inhaled droplet nuclei
- approximately 10% of the inhaled droplet nuclei reach the terminal airways where they can cause infection
- once a droplet lands on something it is no longer infectious
- droplets produced in both coughing and sneezing
Describe the primary infection stage of tuberculosis?
- most often the patient is asymptomatic
- there is a regional lymph node spread and bacteraemia
- with the development of cellular immunity the infection is controlled
- TST becomes positive
Immune defences in tuberculosis are _____ and reinfection is common when the latent infection becomes reactivated
lowered
What has to happen in order for reactivation to occur?
- loss of balance between the immune system and bacilli
- reactivation most often occurs in the lungs but can occur in lymph nodes, pleural space, kidneys, guts and CNS
- the patient is now symptomatic (cough, weight loss, fever and night sweats are all common- if the patient has pulmonary TB they will now be infectious)
What are the first line antibiotics used in tuberculosis therapy?
- isoniazid
- rifampin
- pyrazinamide
- ethambutol
What are mycolic acids?
- mycelia acids are unique/essential mycobacteria cell wall components
- B-hydroxy fatty acids with a long alkyl side chain
- each molecule contains between 60 and 90 carbon atoms
- this is a multi-step synthesis
How does isoniazid work?
- bactericidal to actively growing bacilli
- a prodrug that is converted to active form by bacterial catalase peroxidase
- inhibits mycolic acid synthetase
What are the adverse effects of isoniazid?
peripheral neuropathy
rash
hepatic toxicity
How does rifampin work?
- rifampin is a semi-syntheitic macrocyclic antibiotic
- – rifabutin and rifapentine belong to the same class
- effective against several gram positive and gram negative microorganisms in addition to M. tuberculosis
- inhibits DNA dependent RNA polymerase
- inhibits RNA synthesis
- mycobacterial cell death
- does not bind mammalian RNA polymerase
- froms stable drug enzyme complex
How does pyrazinamide work?
- pyrazine analogue of nicotinamide
- converted by pyrazinamidase to active pyrazinoic acid
- inhibits mycolic acid synthesis, leading to mycobacterial cell death
- active against dormant and semi-dormant mycobacteria in acidic environments
Describe the action of ethambutol?
- synthetic
- causes inhibition of arabinosyl transferase
- inhibits arabinogalactan chain elongation
- inhibits bacterial cell wall synthesis
- reduced mycobacterial cell wall growth (bacteriostatic)
What is the overall “task” of isoniazid?
- bactericidal in extracellular areas with a high oxygen concentration
- important at preventing resistance by killing off rapidly growing bacilli
- high early bactericidal activity
What is the overall “task” of rifampin?
- bactericidal in extracellular areas
- the only drug that is bactericidal in fibrotic areas
- has many drug-drug interactions
- without rifampin- 18 mo of treatment would be required
What is the overall “task” of pyrazinamide?
- important in sterilizing semi-dormant bacteria
- active in an acidic environment
- loses activity as inflammation resolves
- no benefit in using beyond 2 months
- when used with rifampin, the course of therapy is completed in 6 months
What is the overall “task” of ethambutol?
- primarily used to prevent resistance to rifampin when primary resistance to isoniazid may be present
- drug of choice if the organism is sensitive to isoniazid
- not used in renal failure and in children
What is the goal of antibiotic action in the intensive phase? (0-8 weeks)
- goal is to quickly kill the rapidly dividing organism to control disease and render the patient non-infectious and prevent the emergence of drug resistance
- use 4 drugs for the first 8 weeks daily
What is the goal of antibiotic treatment in the continuation phase? (2-6 months)
- sterile the lungs by killing dormant and semi-dormant organisms and prevent relapse
- twice weekly use isoniazid and rifampin DOT
What is the treatment regimen for latent tuberculosis infection?
- isoniazid daily for 9 months
OR - rifampin daily for 4 months
What is the definition of multi-drug resistant tuberculosis?
- resistance to rifampin and isoniazid as well as one other drug
- estimated 4% of patients are multi-drug resistant
What grouping of patients does multi-drug resistant tuberculosis occur most often in?
- in those with weakened immune systems (HIV drugs or immunosuppressants)
- for economic reasons (poverty, lack of healthcare, high rates in the third world)
What is extensively drug resistant tuberculosis?
- tuberculosis that is resistant to rifampin and isoniazid
- resistant to any quinolone
- resistant to any injectable 2nd line agent
- possible as high as 25% of patients with multi-drug resistance are extensively drug resistant
- makes tuberculosis untreatable
What is the mechanism of rifampin resistance?
- rapid resistance due to alteration in DNA dependent RNA polymerase structure
- decreased drug binding
- mycobacterial cell survival
What is the mechanism of isoniazid resistance?
- resistance is due to decreased drug uptake
What is the alternative therapy when there is isoniazid resistance?
- rifampin + pyrazinamide + ethambutol for 6-9 months
- rifampin + pyrazinamide + streptokinase for 6-9 months
- rifampin + ethambutol for 12 months
What is the mechanism of pyrazinamide resistance?
- resistance due to loss of pyrazinamidase
- decreased conversion to pyrazinoic acid
- mycolic acid synthesis occurs
- mycobacterial cell survives
What is the mechanism of ethambutol resistance?
- resistance due to mutations in bacterial arabinosyltransferase gene
- arabinogalactan elongation continues
- mycolic acid synthesis occurs
- mycobacterial cell survives
Tuberculosis infections are generally treated with a combination of 5-7 different drugs. Other than the first line therapies, which drugs can be added?
- protein synthesis inhibitors (cycloserine, capreomycin, kanamycin)
- DNA synthesis inhibitors (fluorowuinolones, amino salicylic acid)
- metabolite synthesis inhibitor (ethionamide)
Situro (bedaquiline) is a new drug used to treat multi-drug resistant tuberculosis. How does it work?
- inhibits mycobacterium ATP synthase
- potent against MDR tuberculosis
- used in combination with rifampicin and pyrazinamide
- approved for use when other drugs are ineffective
- unknown use against latent infections
What are the safety issues associated with sirturo?
- liver toxicity
- prolonged QT
- chest pain
- hemoptysis
- nausea/headache
