EXAM #4: TREATMENT OF MYCOBACTERIA Flashcards
What kind of infection is caused by MAC in the immunocompetent?
Pulmonary
What kind of infection is caused by MAC in the immunocompromised?
Disseminated
What are the important characteristics of Mycobacterium?
1) Rod-shaped
2) Lipid rich cell wall with MYCOLIC ACID
3) Poor gram staining
4) ACID FAST
5) Slow growing*
Makes these bacteria challenging drug targets
What cells can Mycobacterium replicate in?
Macrophages
How is Mycobacterium Tuberculosis transmitted?
Respiratory droplets
What is Latent TB?
Infection with INACTIVE MTB
- Asymptomatic
- PPD positive
- Negative CXR
What is Active TB?
Active infection with MTB
- Symptomatic
- Positive CXR
- Infectious
What are the obstacles to MTB treatment?
1) Slow growing/ dormant
2) Develop resistance
3) Toxicity of drugs
What are the solutions to the obstacles of MTB treatment?
1) Multiple drug regimines
2) Drugs taken regularly
3) Drug therapy for sufficient time
What is direct observed therapy?
Therapy that is directly observed by a public health worker to ensure compliance
List the drugs that are approved for the treatment of TB.
Rifamycin Streptomycin Isoniazid Ethionamide Pyrazinamide
What is the most important drug for treating both latent and active TB? How much resistance is seen to this drug?
Isoniazid
*10% of TB strains are resistant to TB
How is MAC acquired?
- Ingestion of contaminated food and water
- Respiratory droplets (less frequent)
How is the preferred treatment for active TB?
1) RIPE therapy for 8 weeks
2) RI only for 18 weeks
Rifampin
Isoniazid
Pyrazinamide
Ethambutol?
How is latent TB treated?
Isoniazid for 9 months
What is the MOA of Isoniazid (INH)?
Inhibits the synthesis of mycolic acid (cell wall)
*Note that is is given as a Prodrug
What enzyme from MTB converts INH into the active form?
Mycobacterial catalase peroxidase enzyme (Kat G)
What are the resistance mechanisms associated with INH?
1) Kat G mutations–can’t activate the drug
2) Increased mycolic acid synthesis
How is INH metabolized?
Acetylation
What is the implication of “slow acetylation” in INH therapy?
More toxicity seen in slow acetylators
What are the major toxicities associated with INH?
1) Hepatitis
2) Peripheral neuropathy
Note that the hepatitis seen with INH is WORSE in alcoholics
What increases the risk of peripheral neuropathy with INH aside from slow acetylation?
1) Malnourishment
2) Alcoholism
3) DM
4) AIDS
What is the MOA of Rifampin?
Inhibition of RNA synthesis
- Binds bacterial DNA-dependent RNA polymerase
What causes resistance to Rifampin?
Point mutations in bacterial DNA-dependent RNA polymerase
What is the most common side effect associated with Rifampin?
Orange-red color imparted to
- Urine
- Feces
- Sweat
- Tears
….etc.
What important drug-drug interaction is associated with Rifampin?
Increased elimination of many antiretrovirals in HIV
What drug can be substituted for Rifampin in an HIV positive individual with active TB?
Rifabutin
What is the MOA of Pyrazinamide?
Unknown but likely impedes cell wall synthesis
How is Pyrazinamide used in clinical practice?
In combination with other anti-TB drugs–NOT by itself
What is unique about Pyrazinamide in terms of its action?
Prefers an acidic enviornment i.e. prefers to act in acidic marophages treating intracellular MTB
What is the mechanism of resistance to pyrazinamide?
- Pyrazinamide is a prodrug that requires PYRAZINAMIDASE to become active
- Mutations in this enzyme lead to resistance
What adverse effect is associated with Pyrazinamide?
Gout/ Hyperuricemia
What is the MOA of Ethambutol?
Inhibits arabinosyl transferases that are involved in mycobacterial cell wall synthesis
Clinically what is unique about Ethambutol?
Also good for MAC
What causes resistance to Ethambutol?
Mutations in arabinosyl transferases
What are the adverse effects associated with Ethambutol?
1) Retrobulbar neuritis
2) Hyperuricemia
What is Streptomycin?
Aminoglycoside antibiotic
- Interferes with bacterial protein synthesis
What is the utility of Streptomycin in treatment of TB?
Currently used for the treatment of RESISTANT TB
What are the adverse effects associated with Streptomycin?
Ototoxicity
Nephrotoxic
What is a good drug to treat MAC infections (disseminated) in the immunocompromised?
Rifabutin
Outline the combination therapy for MAC infection.
1) Macrolide
2) Rifampin or rifabutin
3) Ethambutol
4) Streptomycin
What are the two forms of Leprosy?
- Lepromatous
- Tuberculoid
What is Lepromatous Leprosy?
- Disfiguring skin lesions
- Negative skin test
- Large number of organisms in tissue
What is the Tuberculoid form of Leprosy?
- Milder
- Hypopigmented plaques
- Positive skin test
- Few organisms
How is Leprosy treated?
1) Dapsone
2) Clofazimine
3) Rifampin
These drugs are taken for YEARS
What is the MOA of Dapsone?
PABA analog that inhibits folate synthesis
What adverse effect is associated with Dapsone?
Non-hemolytic anemia
What is the MOA of Clofazimine?
Bactericidal dye with unknown MOA
What is the adverse effect associated with Clofazimine?
Red-brown to black changes in skin pigmentation
