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Block 4: Mycobacteria-TB


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How do mycobacteria differ from other bacteria?
Their cell wall contains murein. Also enclosed by an inner cytoplasmic membrane.
Why are mycobacteria permeable to both hydrophilic and hydrophobic substances?
Due to the prescence of mycolic acids.
First line agents for TB
Isoniazid-primary agent
Isoniazid (INH) MA
(-) synthesis of mycolic acids
Isoniazid PK
Readily absorbed from GI-diffuses to all tissues and fluids
CNS levels can reach 20-100% of serum concentration

How is INH inactivated? How may this affect sensitivity?
Rate of acetylation may influence individual sensitivity
Clinical usese of INH?
Treatment of clinically manifest dz (in combo w/ethambutol, rifampin, and streptomycin) and for prophylaxis of those whose TB test went from (-) ---> (+)
Adverse Rxns to INH
Peripheral and central neurotoxicity (peripheral neuritis, insomnia, restlessness, muscle twitching)

Hepatotoxicity-hepatitis in 1%

Allergic rxns
HOw do you prevent neurotoxicity from INH?
Coadmin. of B6 (pyridoxine)
Drug interxns of INH?
(-) prahydroxylation of phenytoin
Bacterial resistance (BR) of INH
- 1 in 10^6 - 10^7 (this is high)

No cross resistance between INH and other anti-TB agents
What enzymes activates INH? Why should we know this?
Kat G enzyme
Mutation can confer resistance (Don't you feel better w/this knowledge)
How is rifampin usually given?
In combo w/INH as a first-line agent
MA of rifampin
(-) bacterial DNA dependent RNA polymerase
PK of rifampin
Well absorbed from GI tract
An alarming side effect of rifampin?
Orange-red pee, poop, and spit. :-0
Clinical use of rifampin
Used in combo w/INH, ethambutol, or others

Prophalaxis of meningococcal dz and menigitis due to H.flu and Staph infections (endocarditis, osteomyelitis, nasopharyngeal infection)
Adverse Rxn of rifampin
Jaundice, rashes, thrombocytopenia, nephritis
*When administered less than 2X/wk. get flu-like symptoms (so don't do this)
Drug interxns of rifampin
Reduces t1/2 life of many drugs: anticoagulants, contraceptives, cyclosporine, chloramphenicol, clofibrate, and methadone
What should you do when you prescribe rifampin?
Check other meds-many interactions
Bacterial resistance of rifampin
Similar to INH, no cross resistance
First new TB drug in 25 years, essentially long acting rifampin
TB drug
MA of ethambutol
(-) the synthesis of arabinogalactan

PK of ethambutol
Readily absorbed in GI and excreted in urine
Does not cross BBB except in cases of meningitis
Clinical use of ethambutol
First line treatment w/INH for TB
Adverse Rxns of ethambutol
Notable for few side effects. Can cause optical neuritis--> decreased visual acuity and ability to tell red from green

*Avoid in kids
BR of ethambutol
Develops fairly rapidly when admin. alone--> so don't do it!
Streptomycin and MA, and Adverse Rxns
First effective mycobacterial drug
Note doesn't enter cells--bacteriostatic
Ototoxicity and Nephrotoxicity
Pyramizinamide MA
TB drug that (-) mycolic acid synthesis
PK of Pyrazinamide
Readily absorbed from GI and mainly excreted in urine
Clinical use of Pyrazinamide
Important for short term (6 mo) multiple therapy for TB
Adverse Rxns of Pyrazinamide
BR of Pyrazinamide
Mutation in activation enzyme can confer resistance when administered alone--> that's right so don't do it.
Activation enzyme of Pyrazinamide
Pyrazinamidase (hard right?)
When do we use 2nd line TB drugs?
1. Resistance to 1st line
2. Clincal response to 1st line fails
3. Avoid SE of 1st line
What are the 2nd line TB drugs/
1. Ethionamide
2. Aminosalicylic acid (PAS)
3. Cycloserine
4. Capreomycin, viomycin, kanamycin, amikan, tetracyclines, fluoroquinolones
MA and PK of Ethionamide
Like INH
Adverse rxns to Ethionamide
Poorly tolerated b.c. of GI irritation, metallic taste, and neurologic symptoms (olfactory disturbances, blurred vision)

*Note this is the only drug I found that gives you problems with smelling
BR to Ethiomide
Rapid resistance
No cross resistance w/INH
Similar to sulfonamides
Readily absorbed in GI, excreted in urine

High [] can be reached in urine
How do we prevent the formation of crystalluria in pts. taking PAS
Alkanalize the urine
Adverse Rxns of PAS
GI(anorexia, nausea, diarrhea)
Drug fever
Joint pain
Cycloserine MA
Irreversible (-) of alanine racemase and D-ALA D-ALA syntetase
PK of Cycloserine
Absorbed from GI tract, excreted in urine
Adverse Rxns of Cycloserine
CNS dysfxn (somonolence, headache, tremor) and psychotic rxns (suicidal tendencies, paranoia) (25% of pts)
BR of Cycloserine
No cross-resistance
Capreomycin, Viomycin, Kanamycin, Amikacin
All given parenterally- some cross resistance
Major SE of Tetracyclines and Fluroquinolones
Ototoxicity and Nephrotoxicity
5 guidelines of TB treatment
1. At least 2 drugs

2. At least 6mo: INH, rifampin, and pyrazinamide for 2 mo followed by INH and rifampin for 4 mo.

3. Length depends on combo, more drugs --> less time

4. HIV pts need more intense therapy. Intiate treatment w/4 drugs. INH, rifampin, pyrizinamide, and ethambutol or streptomycin

5. Never use single agent
What kind of therapy do we employ for TB treatment?
Direct observed therapy

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