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Pulmonary > PHARM: Tb Treatment > Flashcards

PHARM: Tb Treatment Flashcards

1
Q

List some reasons why Tb is difficult to treat.

A

1) Organism multiplies slowly (lies dormant for long periods in the host)
2) Survives in a protected intracellular location (can live in macrophages, so antibiotic must cross that barrier)
3) Propensity to develop resistance to single-agent therapy

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2
Q

How do you avoid Tb forming resistance to single-agent therapy?

A

treat with multiple agents for a prolonged course

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3
Q

What is the first line therapy for Tb?

A 
Isoniazid +
Rifampin +
Pyrazinamide +
Ethambutol OR Streptomycin
FOR 8 WEEKS
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4
Q

For latent Tb infections, what is the quickest, most adhered-to treatment regimen?

A

Isoniazid + Rifapentine (INH-RPT)

for three months once weekly

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5
Q

Who should NOT get INH-RPT for latent Tb infections?

A

Children <2
HIV patients
pregnant women
people with resistance to isoniazid or rifapentine

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6
Q

What are the two phases of Tb treatment?

A

1) Initial phase lasting for 8 weeks

2) Continuation phase lasting for 18 weeks

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7
Q

What is the preferred “continuation phase” therapy for active Tb?

A

Daily or twice-weekly Isoniazid and Rifampin for 18 weeks

can be once weekly in HIV patients who have good response to initial phase treatment

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8
Q

What must many physicians order so that patient is compliant to Tb therapy?

A

DOT (directly observed therapy)

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9
Q

What is the MOA of Isoniazid?

A

Penetrates host cells in order to interefere with cell wall synthesis (mycolic acid synthesis). It is bactercidal for rapidly dividing bacilli and bacteriostatic for slow growing bacilli.

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10
Q

What does isoniazid form in rapidly growing bacilli infections?

A

extracellular cavitary lesions

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11
Q

What does isoniazid form in slow growing bacilli infections?

A

closed caseous lesions with macrophages

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12
Q

What are the mechanisms of resistance to isoniazid?

A

Rapidly emerging resistance (so never use with a single agent) due to:

  • Inability to take up drug
  • Alteration of target enzyme
  • Overproduction of target enzyme
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13
Q

What is the route of administration, absorption, and secretion of isoniazid?

A

Administration: orally or IM
Absorption: GI tract
Secretion: 75% of drug and metabolites secreted in urine

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14
Q

What is interesting about the distribution of isoniazid?

A

can cross meninges into CSF and can cross placenta and pass through breast milk

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15
Q

Where does the metabolism of isoniazid occur?

A

liver (primarily by acetylation that can be fast or slow depending on patient’s genetics)

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16
Q

What are the two major adverse effects of isoniazid?

A

Peripheral neuropathy

Hepatotoxicity

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17
Q

What are drug interactions of isoniazid?

A

1) Antacids with aluminum salts (gastric emptying altered)
2) Corticocosteroids (reduce efficacy)
3) Inhibits CYP450, so metabolized drugs will be in too high of concentration

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18
Q

List the rifamycins.

A

Rifampin
Rifabutin
Rifapentine

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19
Q

What is the MOA of rifampin?

A

inhibits RNA synthesis (by binding to and inhibiting beta subunit of mycobacterum DNA-dependent RNA polymerase) in intracellular or extracellular myobacteria

BACTERICIDIAL

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20
Q

What are methods of resistance to rifampin?

A

RESISTANCE DEVELOPS RAPIDLY (so never give as a single drug) via:
Altered beta subunit

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21
Q

What is the route of administration, absorption, and secretion of rifampin?

A

Administration: oral
Absorption: GI and impaired by food or para-aminosalicyclic acid
Secretion: bile (30% unchanged) and some by renal tubular secretion

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22
Q

Where is rifampin metabolized?

A

Liver (deacetylation)

23
Q

What is a strange adverse effect of Rifampin?

A

orange-red body fluids

24
Q

What is the hepatotoxicity associated (rarely) with rifampin due to?

A

Slow acetylators or patients with chronic liver disease may get hepatitis

25
Q

What are some drug interactions associated with rifampin?

A

CYP450 inducer, so decreases half life of drugs like prednisone
Oral anticoagulants and contraceptives less effective (because rifampin is hepatic enzyme inducer)
Probenecid increases serum levels of rifampin

26
Q

What is the MOA of ethambutol?

A

Disrupts cell wall synthesis (IN RAPIDLY DIVIDING BACILLI ONLY) by inhibiting arabinosyl transferase (necessary for arabinogalactan synthesis to make peptidoglycan units of cell wall) and leading to increased cell wall permeability

27
Q

Is ethambutol bactericidal or bacteriostatic?

A

Bacteriostatic (but may be cidal at high doses)

28
Q

What is the route of administration, absorption, and secretion of ethambutol?

A

Administration: oral
Absorption: 75% in GI tract
Secretion: excreted in urine (need to reduce dose with renal failure)

29
Q

What is interesting about the distribution of ethambutol?

A

Concentrates in kidneys, lungs, and saliva but can cross placenta, BBB into CSF, and into breast milk

30
Q

What are the adverse reactions to ethambutol?

A

Optic neuritis (decreased visual acuity and loss of color discrimination that is reversible over time) DOSE RELATED
Allergic reactions
Hyperuricemia (with or without gout)

31
Q

What are some drug interactions of ethambutol?

A

Aluminum containing antacids (reduce absorption)

32
Q

What is the MOA of pyrazinamide?

A

unknown (converted to metabolite that decreases the pH below which Tb can grow) and can be bacteriostatic or bactericidal depending on dose

33
Q

In what environment does pyrazinamide work best?

A

intracellular sites where Tb grows slowly (like within macrophages)

34
Q

how does pyrazinamide get converted to its active metabolite?

A

the bacilli release an enzyme that converts it

35
Q

What is the route of administration, absorption, and secretion of pyrazinamide?

A

Administration: oral
Absorption: GI (quickly)
Secretion: glomerular filtration

36
Q

Where is pyrazinamide metabolized?

A

hydrolyzed in the liver to pyrazinoic acid

37
Q

Where is pyrazinamide distributed?

A

CSF, breast milk, throughout the body

38
Q

List some adverse effects to pyrazinamide.

A
  • Dose related hepatotoxicity
  • Mild, non-gouty arthralgias secondary to
  • Hyperuricemia (due to inhibition of urate excretion)
39
Q

What is MDR-Tb?

A

Multidrug-Resistant Tb (form of Tb that can no longer be killed by at least the two best antibiotics (INH and RIF).

40
Q

What are some agents used in MDR-Tb?

A

Cycloserine

Ethionamide

41
Q

Wha tis the MOA of cycloserine?

A

Structural analog of D-Ala (important for cell wall peptidoglycan synthesis) so it gets incorporated into cell wall (weak wall that eventually lyses) and blocks synthesis of more d-ala

42
Q

What is the route of administration, absorption, and secretion of cycloserine?

A

Administration: oral
Absorption: GI (quickly)
Secretion: urine (dose adjust for renal failure)

43
Q

Where does cycloserine distribute?

A 
all over (lungs, pleural and synovial fluids)
placenta
breast milk
aminotic fluid
CSF
44
Q

What are the adverse effects of cycloserine?

A 
CNS problems (especially with alcohol use)
seizures
suicidal thoughts
headache
tremor
45
Q

What is the MOA of ethionamide?

A

inhibits peptide synthesis (structural analog of isoniazid)

Bacteriostatic or cidal (conc. dependent)

46
Q

What is the route of administration of ethionamide?

A

Administration: oral

47
Q

What is the metabolism of ethionamide?

A

Extensive hepatic metabolism (inactive prodrug that is activated by a mycobacterial redux system)

48
Q

Why do we reserve ethionamide for last line therapy of Tb?

A

Toxicity:
GI (anorexia, nausea)
Neurologic (depression, dizziness relieved with pyridoxine)
Hepatic toxicity

49
Q

What is XDR-Tb?

A

Extensively drug-resistant Tb (resistant to INH, RIF, and most of the alternative drugs used to treat MDR-Tb)

50
Q

What drugs are used to treat XDR-Tb? How long?

A

Fluoroquinolone +
Amikacin, Kanamycin, or Capreomycin

(needs up to 2 years of treatment!!!)

51
Q

What is the MOA of capreomycin?

A

Unknown but bacteriostatic

52
Q

What is the ROA of capreomycin?

A

IM

53
Q

What are adverse effects of capreomycin?

A

Nephrotoxic (proteinuria, nitrogen retention)

Ototoxic (hearing loss, tinnitus, etc.)

Pulmonary (34 decks)

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