P: Chemo/tb/fungal Drugs

Front 1

Mycobacteria are frequently intracellular (mostly in macrophages)
The organism is extremely slow growing (a culture takes nearly two weeks to grow turbid in the laboratory)
Tubercular nodules are poorly perfused

....these 3 properties mean that therapy for TB usually lasts ___ but can extend to ___.

Back 1

6-9m; 2y

Front 2

What is the biggest infectious dz killer worldwide?

Biggest risk factor for contraction?

Mainstay of tx?

MDR-TB is resistant to two of the most effective 1st line drugs, ____ and _____.

XDR-TB is resistant to what?

Back 2

TB

AIDs pts have a 500x greater incidence.

Multidrug regimens.

Isonaiazid and rifampin.

the above, plus any fluoroquin and at least one of the three injectable 2nd-line aminoglycosides.

Front 3

Why do we use multidrug Tx for TB?

In theory, should this work most of the time?

Why does resistance still arise?

Current hopeful solution?

Back 3

TB bacteria gain resistance thru spontaneous resistance muts, which have probabilities. TB nodules can have up to 10^9 cells, so we combine the two drugs to combine the probabilites --> becomes greater than the # of TB cells.

Yes, it should. It should prevent the evolution of resistance, or at least keep it to a min.

Monotherapy in 3rd world, Pt non-compliance.

DOT --> nearly 100% cure rate when implemented in NYC.

Front 4

Class the following drugs as 1st or 2nd line drugs for TB:

Amkiacin
Ethionamide
Ethambutol
Ciprofloxacin
Isoniazid
D-cycloserine
Streptomycin
Rifampin
Pyrazinamide

When are 2nd lines used?

Back 4

1st:
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol

2nd:
Streptomycin
D-cycloserine
Ethionamide
Ciprofloxacin
Amikacin

Only in cases of recurrent or MDR-TB.

Front 5

What is the mainstay of TB tx, and is also used as a single agent for prophylaxis following exposure?

How does it work? Does it penetrate cells (like macrophages)?
Is is selective for mycobacterial cells?

Back 5

Isoniazid (INH)

prodrug that is actv by KatG (catalase). Actv form covalently inhibits enzymes involved in synth of mycolic acid --> necessary for mycobact cell wall.

Yes.

Yes, it is.

Front 6

How is INH metabolized?
- Toxicities? Susceptible populations?
- Drug interactions?
- resistances?

Back 6

by acetylation dependent upon genetic factors... thus those who do it slowly may see more toxic effects when they have concurrent renal issues.

Potentially fatal hepatotoxicity (most common; 20% of pts.)
- freq in elderly and alcoholics
Peripheral & CNS neuropathy
- due to Vit B6 depletion
+ can be counteracted w/ pyridoxime (VitB6)

*Induces* P450

overproduction of InhA --> low lvl resistance
mut/del of katG --> high lvl resistance

Front 7

What does KatG do, re: 1st line anti-TB tx?

Which 1st line TB drug is also used for prophylaxis of meningitis caused by N. meningitidis and H. influenzae?

Back 7

Activates INH.

Rifampin

Front 8

rifampin:
- mech
- toxicities
- drug interactions

Back 8

- inhibits DNAdepRNApoly
- Hepatotoxicity, esp. w/ INH
- *induces* P450; can cancel effects of oral contraceptives.

Front 9

Ethambutol
- mech
- toxcities
- resistances

Back 9

- inhib synth of arabinogalactan, an ess. cmpt of TB cell wall.
- reversible optic neuritits, including R/G discrimination

- overexp of the enz that synth arabinogalactan
- muts that lower affin of the enz for ethambutol

Front 10

Pyrazinamide
- mech
- toxicities
- mech/speed of resistance

Back 10

- it is converted to pyrazinoic acid by pncA-encoded pyrizinamidase... but we don't know how the actv drug works.
- hepatotoxicity & hyperuricemia
- unknown, but happens quickly in single therapy.

Front 11

Describe the CDC regimen for TB tx.

Back 11

Isoniazid, rifampin, ethambutol*, and pyrizinamide for 2 months
INH and rifampin for the next 4 months

*Ethambutol may be discontinued when results of drug susceptibility indicate no drug resistance

Front 12

Where is mycobacterium-Avium complex (MAC) primarily found?
- Tx?
+ duration?
- what is used in prophylaxis in at risk pts?

Back 12

in 15-40% of pts w/ advanced AIDS + T-counts <100/mm3
- ethambutol plus azithromycin or clarithromycin
+ extends for life
Rifabutin (derivative of rifampin) is used in non-infected AIDs pts with low T-cell counts.

Front 13

What is the most effective antifungal agent in use? What are issues w/ it? What is synergistic with it?

Back 13

Amphotericin B (AMB)
- difficult to administer
- many side effects
- Flucytosine

Front 14

How does AMB work?
High or low therapeutic index?

Back 14

b/ cells membranes, forms a cmplx w/ ergosterol, makes a transmembrane pore.
- AMB has one side hydrophobic and the other polar.

...all sorts of ions leak out of the pore --> osmotic instability --> cell death.

Very low.

Front 15

PharmacoK of AMB? Is there an advantage of the liposomal form?

Back 15

given by slow IV infusion; rapidly sequestered in tiss (slowly released)
- hl = 15d
- [CSF] < [blood]

yes, it increases therapeutic lvls and somewhat \toxicity

Front 16

What is used in concert with flucytosine for:
Cryptococcus meningitis
Candidia infections

How about used as a single agent for coccidioides meningities?

What are some of the toxicities of this agent?

Back 16

AMB, AMB (intrathecal admin)

Potent nephrotoxin (damages renal tubules)
- must be careful when giving other nephrotoxic drugs (e.g., aminoglycosides, cyclosporin)

Hypokalemia: often K+ supplement is required

Hypersensitivity:
- fever, chills, vomiting, headache
- can try NSAIDs to reduce these effects

Front 17

What are some of the mechanisms of resistance for AMB? Is it rare or common?

Back 17

development of resistance during therapy is Very rare.

Resistance is due to \lvls of ergosterol or alteration of it's structure.

Front 18

5-Fluorocytosine (Flucytosine)
- mech
- often used alone?
- effective when combined with what?
- toxicities of prolonged use or high concentrations?
- resistance mechanisms?

Back 18

- taken up by fungal cell --> 5-FU --> FdUMP: cmplxs w/thymidylate synthase and blocks DNA synth.

- rarely used alone b/c of resistance.
- effective with AMB in candida and cryptococcus tx.
- BM depression, hair loss, GI distress, hepatotoxicity
- muts in cytosine permease or cytosine deaminase.

Front 19

What are the Azoles?
- mech?
- uses?
+ alternative to AMB + flucytosine in what usages?

Back 19

Ketoconazole, Fluconazole, Itraconazole
- fungistatic: block ergosterol synth by inhibiting 14-{-demtheylase, a P450-dependent enzyme
- blastomycosis, histoplasmosis, candidiasis
+ coccidiodal and cryptococcal meningitis.

Front 20

Which is the only Azole that penetrates the CNS?

What are some general toxicities of Azoles?

Interactions?
Resistances?

Back 20

Fluconazole

all induce vomiting, diarrhea, and rashes, as well as occasional impairment of hepatic function.

Can inhibit metabolism of P450 stuff, unsuprisingly.

- Overproduction/alteration of 14-{-demethylase.
- efflux pump