Antimicrobial 3: Antimycobacterials Flashcards
Name 2 main mycobacterial infections in humans:
tuberculosis (TB):
chronic infections caused by Mycobacterium tuberculosis
leprosy
chronic infections caused by Mycobacterium leprae
Mycobacterium are capable of surviving inside
macrophages after phagocytosis
tuberculosis (TB)
Characteristics
• TB usually affects the lungs and is associated with
chronic cough with blood-containing sputum
• Tuberculosis results almost exclusively through
inhalation of airborne particles that contain M.
tuberculosis
• Dispersed/spread through forced respiratory
maneuvers by those with active TB (e.g. coughing,
singing)
tuberculosis (TB)
Symptoms
Active pulmonary tuberculosis
symptoms:
- Most common symptom: Cough (becomes more
productive as disease progresses) - May have no symptoms aside from ”not feeling well”,
anorexia, fatigue, weight loss
Leprosy
Characteristics
• Leprosy mainly affects the skin and peripheral nerves
• Leprosy is an ancient disease that causes a chronic
disfiguring illness with long latency (2 types:
paucibacillary or multibacillary)
- Paucibacillary: T cell response dominated by interferon gamma - enhances macrophage’s ability To eliminate mycobacteria- treatment not as long
- Multibacillary: T cell response dominated by IL-4 response which can interfere with IF-gamma, macrophages fail to eradicate as good
• Spread person to person through nasal droplets and
secretions
Leprosy
Symptoms
Symptoms include non-pruritic rash, numbness and weakness of areas controlled by affected nerves
Not highly contagious - believed to be contagious due to appearance
Leprosy
Name 2 types of leprosy:
- tuberculoid leprosy
- lepromatous leprosy
Depending on type, different presentation of skin lesions, skin macules, papules, plaques
TB
Pharmacotherapy
- Initial phase of treatment includes isoniazid, rifampicin and pyrazinamide (and possibly ethambutol) for 2- months
- Continuation phase includes treatment with isoniazid and rifampicin for 4-months
• Combination therapy is used to avoid the development of drug resistance
Leprosy
Pharmacotherapy
- Tuberculoid leprosy treated with dapsone and
rifampicin for 6-months - Lepromatous leprosy treated with dapsone,
rifampicin, and clofazimine for 2-years
• Combination therapy is used to avoid the
development of drug resistance
Mycobacterial Cell Wall
Characteristics
• The mycobacterial cell wall is composed of a
peptidoglycan (PG) - arabinogalactan (AG) - mycolic
acid (MA) structure
- classified as G+ with peptidoglycan
• Mycobacteria, similar to gram negative bacteria, do
NOT retain the crystal violet stain. However, they are
classified as acid-fast gram positive bacteria due to
their lack of an outer cell membrane
tuberculosis (TB)
First-line Agents
Combination therapy is usually mandatory for TB to
decrease the probability of the emergence of resistant organisms
- Isoniazid
- Rifampicin
- Ethambutol
- Pyrazinamide
tuberculosis (TB)
Second-line Agents
Combination therapy is usually mandatory for TB to
decrease the probability of the emergence of resistant organisms
- Capreomycin
- Cycloserine
- Streptomycin
Note: these agents are used treat infections likely to be
resistant to first line agents or when first line agents are
abandoned due to adverse effects.
tuberculosis (TB) Agent
Isoniazid
Pharmacology
A prodrug that is activated by bacterial enzymes (katG) and subsequently inhibits synthesis of mycolic acids, an important component of the mycobacterium cell wall
- converted to isoniazid NAD complex, interferes with final step of mycolic acid syth, struggle to make cell wall
tuberculosis (TB) Agent
Isoniazid
AE
- Can cause * hemolytic anemia in people with glucose-
6-phosphate dehydrogenase deficiency - Other adverse effects include allergic skin eruptions,
fever, hepatotoxicity, arthritic symptoms & vasculitis
tuberculosis (TB) Agent
Rifampicin (aka Rifampin)
Pharmacology
Binds to and inhibits DNA-dependent RNA polymerase
only in prokaryotic cells
(not mammalian)
- mycobac cannot transcribe a mRNA to make proteins
tuberculosis (TB) Agent
Rifampicin (aka Rifampin)
AE
- Acute interstitial nephritis (rare)
- Orange tinge to saliva, tears, sweat
- (widely distributed in body fluids)
- Are infrequent but include skin eruptions, fever, GI
disturbances, & liver damage with jaundice
tuberculosis (TB) Agent
Ethambutol
Pharmacology
Only affects mycobacteria (likely via inhibiting arabinosyl transferase to impair mycobacterial cell wall synthesis)
- transfers arabinose residue of arabinoglactan (AG) to mycolic acid, attachments so cell wall cannot be made
tuberculosis (TB) Agent
Ethambutol
AE
- optic neuritis (red-green color blindness),
- peripheral neuropathy
- rash
tuberculosis (TB) Agent
Pyrazinamide
Pharmacology
Analog of nicotinamide (prodrug for pyrazinoic acid)
- Is tuberculostatic at acidic pH and inhibits bacterial
fatty acid synthesis (likely via inhibiting fatty acid
synthase that elongates fatty acids) - when macrophage engulfs bac, it is contained with lysosomes which has acidic pH that can activate the drug and kill bacteria
tuberculosis (TB) Agent
Pyrazinamide
AE
- High doses can lead to serious * hepatic damage (must monitor enzymes)
- gout: interefere with excretion of uric acid, increase levels
- GI upset
- malaise
- fever
tuberculosis (TB) Agent
Capreomycin
Pharmacology
A peptide antibiotic thought to act via binding to the 70S ribosomal unit and inhibiting protein synthesis
tuberculosis (TB) Agent
Capreomycin
AE
- kidney damage
- auditory nerve injury (can lead to deafness and
ataxia)
- auditory nerve injury (can lead to deafness and
not given with other antibiotics with ototoxicity
tuberculosis (TB) Agent
Cycloserine
Pharmacology
Broad-spectrum antibiotic that competitively inhibits bacterial cell wall synthesis by preventing formation of tripeptide side- chains of N-acetylmuramic acid, which is a major building block for peptidoglycan
prevent D-Ala D-Ala dipeptide that forms with N-acetylmuramic acid - tripeptide as building blocks for peptidoglycan
tuberculosis (TB) Agent
Cycloserine
AE
- primarily CNS actions, such as headache, irritability,
depression, convulsions & psychotic states
Leprosy Agent
Drugs
- Rifampicin
- Dapsone
- Clofazimine
Leprosy Agent
Dapsone
Pharmacology
Chemically related to sulfonamides and thus likely acts via inhibiting bacterial folate synthesis
prevents purine/pyr synth
Leprosy Agent
Dapsone
AE
- hemolysis of red blood cells
- methemoglobinemia
- anorexia
- nausea
- vomiting
- allergic dermatitis
- neuropathy
May induce * Lepra reactions (exacerbation of lepromatous regions)
Leprosy Agent
Clofazimine
Pharmacology
Is a dye with proposed action against leprosy bacilli involving action on DNA (may also be anti-inflammatory)
- can be used with dapsone with can cause inflammation
not really known
Leprosy Agent
Clofazimine
AE
- reddish colour of the skin and urine (it’s a dye)
- lesions can be green bluish
- GI upset
- nausea
- headache
Llong-lived as the mycobacterium can survive within macrophages after being phagocytosis, what does this describe?
Mycobacterial infections
What are the First-line therapies for TB?
- isoniazid
- rifampicin,
- ethambutol
- pyrazinamide
Leprosy is generally curable now and treated with what drugs?
- rifampicin
- dapsone
- clofazimine
Why treatment for TB and Leprosy always involves combination therapy?
to reduce risk for drug resistance
