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CPR > Anit fungal/influenza/TB > Flashcards

Anit fungal/influenza/TB Flashcards

1
Q

Amphotericin B - MOA

A

binds ergosterol, inserts pores into fungal membrane, leakage of intracellular ions causes death

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2
Q

What is the cholesterol of fungi?

A

ergosterol - found in cell membrane of fungi

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3
Q

Amphotericin B - Spectrum

A 
• Yeasts
 - Candida albicans
 - Cryptococcus neoformans
• Organisms causing endemic mycoses
 - Histoplasma capsulatum 
 - Blastomyces dermatitidis   
 - Coccidioides immitis
• Pathogenic molds
 - Aspergillus fumigatus
 - Agents of mucormycosis
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4
Q

What anti-fungal has the broadest sprectum of activity?

A

amphotericin B

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5
Q

Amphotericin B - resistance

A

fungi that can alter their ergosterol, which makes it harder for the drug to bind

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6
Q

Amphotericin B - PK

A
  • give by IV for systemic infections

- poorly absorbed in GI (only orally given with GI infection)

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7
Q

Amphotericin B - AEs

A

a. immediate rxn: Fever, chills, muscle spasms, vomiting, headache, and hypotension
b. long term rxn: renal damage, anemia, seizures

*renal damage occurs in almost all pts

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8
Q

How can we prevent immediate AEs of amphotericin B?

A

• slowing the infusion rate or decreasing the dose
• Premedication with corticosteroids, antipyretics, antihistamines, or meperidine can be
helpful in prevention

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9
Q

Flucytosine - MOA

A
  • taken up by fungal cell via cytosine permeate
  • becomes FdUMP (inhibits DNA synthesis) and FUTP (inhibits RNA synthesis

*human cells can’t convert it, so no damage to our cells

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10
Q

What can we pair flucytosine with to enhance action?

A

Amphotericin B

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11
Q

Flucytosine - Spectrum

A

• C. neoformans
• Some Candida spp.
• Dematiaceous molds that cause chromoblastomycosis
• combo with:
- Amphotericin B for cryptococcal meningitis
- Itraconazole for chromoblastomycosis
• Limited clinical utility of flucytosine monotherapy in fluconazole-resistant candidal UTIs

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12
Q

Flucytosine - Resistance

A

• Altered metabolism of flucytosine

*Develops rapidly in flucytosine monotherapy

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13
Q

Flucytosine - PK

A
  • oral formulation

- widely distributed in body (even CNS - unlike amphotericin B)

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14
Q

Flucytosine - AE

A
  • due to metabolism of flucytosine to 5-FU outside the fungal cell (via intestinal flora)
  • BM toxicity with anemia, leukopenia, thrombocytopenia
  • derangement of liver enzymes (uncommon)
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15
Q

What are the two classes of Azoles?

A 
• Imidazole
   - Ketoconazole 
• Triazoles
  - Itraconazole
  - Fluconazole
  - Voriconazole 
  - Posaconazole

*Ketoconazole has less selectivity for human cells versus the triazoles

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16
Q

Azoles - MOA

A
  • inhibit fungal P450 enzymes –> decreased ergosterol synthesis
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17
Q

Azoles - Spectrum

A
  • Many species of Candida
  • C. neoformans
  • The endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis)
  • The dermatophytes
  • Aspergillus spp. infections
  • Intrinsically amphotericin B-resistant organisms such as P. boydii
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18
Q

Which three azoles can be used in aspergillus infections?

A

• Itraconazole, posaconazole, and voriconazole

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19
Q

Azole - Resistance

A
  • up regulation of fungal P450 enzymes –> standard dose doesn’t work
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20
Q

Azole - AE

A
  • minor GI problems
  • liver enzyme problems
  • drug interactions (due to minimal effect on human P450s)
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21
Q

Ketonconazole

A
  • Greater propensity to inhibit mammalian cytochrome P450 enzymes
  • more common for dermatological functions
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22
Q

Itraconazole

A
  • oral and IV options
  • poor CSF penetration
  • Spectrum
    a. Dimorphic fungi
    b. Histoplasma, Blastomyces, and Sporothrix
    c. Aspergillus spp.
    d. Dermatophytoses and onychomycosis
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23
Q

What azole has reduced function when taken with Rifamycins?

A

Itraconazole

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24
Q

Fluconazole

A
  • high oral
  • good CSF penetration
  • Spectrum
    • Azole
    • cryptococcal meningitis
    • mucocutaneous
      candidiasis
      • No activity against Aspergillus spp. or other filamentous fungi
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25
Q

Which azole has the widest spectrum?

A

Fluconazole

*also has least effect on liver enzymes

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26
Q

Voriconazole

A
  • oral and IV
  • inhibits human CYP3A4
  • AEs: rash, inc hepatic enzymes, visual probs, photosensitivity dermatitis
  • Spectrum:
    • Candida spp. (Includes fluconazole-resistant species such as Candida krusei)
    • Dimorphic fungi
    • Aspergillus spp.
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27
Q

Why do you have to really worry about drug interactions and doses when taking voriconazole?

A

it inhibits human CYP3A4

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28
Q

What azole is the tx of choice of Aspergillus? what azole has the broadest spectrum?

A

a. Voriconazole

b. Posaconazole

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29
Q

Posaconazole

A
  • liquid oral, oral tablet, IV
  • Inhibits mammalian CYP3A4
  • Spectrum:
    • most species of Candida
      and Aspergillus
    • Only azole with significant
      activity against
      mucormycosis
    • Currently uses as: Salvage
      therapy for invasive
      aspergillosis;
  • Prophylaxis…
    • During induction
      chemotherapy for
      leukemia
    • In allogenic bone marrow
      transplant patients with
      graft-versus-host disease
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30
Q

Echinocandins - MOA

A
  • Inhibit synthesis of bet (1-3)-glucan at the fungal cell wall by inhibiting glucan synthase
  • This disrupts the fungal cell wall –> fungal cell death
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31
Q

Echinocandins - Spectrum

A
  • Candida spp. and Aspergillus spp.

* No coverage of C. neoformans or agents of zygomycosis / mucormycosis

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32
Q

What are the three specific echinocandins?

A

Caspofungin, Micafungin, and Anidulafungin

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33
Q

Caspofungin

A
  • Disseminated and mucocutaneous candidal infections

* Invasive aspergillosis (Not primary therapy)

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34
Q

Micafungin

A
  • Mucocutaneous candidiasis
  • Candidemia
  • Prophylaxis of candidal infections in bone marrow transplant patients
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35
Q

Anidulafungin

A

• Esophageal candidiasis and invasive candidiasis, including candidemia

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36
Q

Echinocandin - Resistance

A
  • point mutations in gluten synthase
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37
Q

Echinocandin - PK

A
  • parenteral (IV)
  • Half-life
    a. Caspofungin: 9-11 hours
    b. Micafungin: 11-15 hours
    c. Anidulafungin: 24-48 hours
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38
Q

Echinocandin - AE

A
  • minor GI effects

- flushing

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39
Q

Neuraminidase Inhibitors - MOA

A
  • competitive inhibitors of viral neuraminidase
  • results in bunching of newly release influenza virions
  • halts spread of disease within respiratory tract
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40
Q

Neuraminidase Inhibitors Class members

A
  • Oseltamivir
  • Zanamivir
  • Peramivir
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41
Q

Neuraminidase Inhibitors - Spectrum

A
  • Influenza A and B strains
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42
Q

Neuraminidase Inhibitors - Resistance

A

rare

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43
Q

Neuraminidase Inhibitors - PK

A
  • early administration is key
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44
Q

Neuraminidase Inhibitors - AE

A
  • increase risk of hallucinations, delirium, and abnormal behavior
45
Q

Oseltamivir

A
  • Oral administration
  • Prodrug activated by hepatic esterases
  • Nausea, vomiting, and headache
  • Fatigue and diarrhea more common with prophylactic use
46
Q

Zanamivir

A
  • Administered directly to respiratory tract by inhalation
  • Cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort

*contraindicated in pts with underlying airway disease

47
Q

Peramivir

A
  • Administered as a single IV dose
  • Diarrhea (most common)
  • Skin or hypersensitivity reactions (less common)
48
Q

Adamantanes class members

A

amantadine and rimantadine

49
Q

Adamantanes - MOA

A

• Block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing replication

50
Q

Adamantanes - Spectrum

A

Influenza A

51
Q

Adamantanes - Resistance

A
  • high rates in H1N1 and H3N2
52
Q

Adamantanes - PK

A
  • oral
53
Q

Adamantanes - AE

A
  • Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, and light-headedness
  • Birth defects have been reported after exposure during pregnancy 
 !!!!
54
Q

What drugs do you give as first line tx of TB?

A
  • Rifampin (!!)
  • Isoniazid (!!)
  • Pyrazinamide (shortens tx)
  • Ethambutol (more coverage)

*RIPE

55
Q

When is Ethambutol not needed in TB tx?

A

when the strand is known to not be resistance to Rifampin and Isoniazid

56
Q

Isoniazid - MOA

A
  • inhibits Mycotic acid synthesis

- activated by KatG

57
Q

Isoniazid - Resistance

A
  • O/E of inhA
  • Mutatino of deletion of katG gene
  • Promoter mutations resulting in O/E of aphC
  • Mutations in kasA
  • resistance quickly develops if used as a mono therapy
  • Ethionamide has the same resistance
58
Q

Isoniazid - Clinical

A
  • oral med given daily

- works alone in pts with latent infection

59
Q

Isoniazid - AE

A

• Related to dosage and duration of administration
• Isoniazid-induced hepatitis is the most major toxic effect
- Development of isoniazid hepatitis contraindicates further use of the drug
• Peripheral neuropathy
- More likely to occur in slow acetlylators
- Neuropathy occurs due to pyridoxine deficiency

60
Q

If a patient has a B6 deficiency, what drug should you be cautious to give them?

A

Isoniazid - peripheral neuropathy (though reversed if pt is given B6)

*Isoniazid and pyridoxine share a similar structure and isoniazid administration promotes the excretion of pyridoxine

61
Q

What is a contraindication of Isoniazid?

A

further use after hepatitis develops

62
Q

Rifampin - MOA

A
  • Inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA polymerase
  • can kill intracellular organisms and those sequestered in
    abscesses and lung cavities
  • strong inducer of P450
63
Q

Rifampin - Resistance

A
  • point mutations in rpoB (gene for beta subunit)
64
Q

Rifampin - Clinical Note

A
  • must be administered with another anti-TB drug to prevent emergence of drug resistance
65
Q

Rifampin - AE

A
  • Harmless orange color to urine, sweat, and tears
  • May permanently stain soft contact lenses
  • Occasional adverse effects include rashes, thrombocytopenia, and nephritis
66
Q

Ethambutol - MOA

A
  • Inhibition of mycobacterial arabinosyl transferases

* These are encoded by the embCAB operon

67
Q

Ethambutol - Resistance

A
  • Mutations resulting in overexpression of emb gene products or within the embB structural gene
  • Overexpression overwhelms the action of ethambutol and mutations within the structure prevent ethambutol binding
68
Q

Ethambutol - AE

A
  • retrobulbar neuritis (results in loss of visual acuity and red-green color blindness)
69
Q

What is the contraindication of ethambutol?

A

children to young to permit assessment of visual acuity and red-green color discrimination

70
Q

Pyrazinamide - MOA

A
  • Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase
  • Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions
71
Q

Pyrazinamide - Resistance

A
  • impairs uptake

- mutations in pica that impair conversion to active form

72
Q

Pyrazinamide - AE

A
  • Hepatotoxicity (1-5%), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia
73
Q

When are second line TB meds used?

A
  • Cases of resistance to first-line agents
  • Failure of clinical response to conventional therapy
  • Serious treatment-limiting adverse drug reactions to first line agents
74
Q

Streptomycin - MOA

A
  • protein synthesis inhibitors
75
Q

Streptomycin - Resistance

A
  • penetrates cells poorly

- active against extreellular tubercle bacilli

76
Q

Streptomycin - Clinical Notes

A
  • can replace ethambutol
77
Q

Streptomycin - AE

A

• Ototoxic and nephrotoxic
• Vertigo and hearing loss are the most common
- Hearing loss can be
permanent
• Toxicity reduced by limiting therapy to no more than 6 months

78
Q

Ethionamide - MOA

A
  • blocks synthesis of mycotic acids

* chemically related to isoniazid

79
Q

Ethionamide - AE

A
  • gastric irritation

- neurologic symptoms (relieve with B6)

80
Q

Capreomycin - MOA

A
  • peptide protein synthesis inhibitor
81
Q

If a drug is resistant to streptomycin, what drug might work?

A

Capreomycin

82
Q

Capreomycin - AE

A
  • Nephrotoxic and ototoxic

* Tinnitus, deafness, and vestibular disturbances can occur

83
Q

Cycloserine - MOA

A

• Inhibits cell wall synthesis by inhibiting the incorporation of D-alanine into the peptidoglycan
pentapeptide by inhibiting alanine racemase and D-alanyl-D-alanine ligase

84
Q

Cycloserine - AE

A
  • Peripheral neuropathy and CNS dysfunction, including depression and psychoses
  • headaches, tremors, and convulsions

*Pyridoxine (vitamin B6) ameliorates the neurologic toxicity

85
Q

Aminosalicyclic Acid - MOA

A

• Folate synthesis inhibitor active exclusively against M. tuberculosis

86
Q

Aminosalicyclic Acid - AE

A

• GI adverse effects, peptic ulceration, and hemorrhage
• Hypersensitivity reactions can occur 3-8 weeks after treatment
- Symptoms include fever, joint pains, skin rashes, hapatosplenomegaly, hepatitis, adenopathy, and granulocytopenia

87
Q

Kanamycin/Amikacin - MOA

A
  • protein synthesis inhibitors
88
Q

Kanamycin/Amikacin - Resistance

A

amikacin has cross resistance with kanamycin

89
Q

Kanamycin/Amikacin - Clinical Note

A

• Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multi-drug resistant strains

90
Q

Kanamycin/Amikacin - AE

A

• Ototoxic and nephrotoxic
• Vertigo and hearing loss (most common)
- Hearing loss can be permanent

91
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - MOA

A
  • fluoroquinolone antibiotics

- inhibit topoisomerase II and IV

92
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - Resistance

A
  • point mutations in DNA gyrase (aka topoisomerase II)
93
Q

Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - AE

A
  • Abdominal discomfort, nausea, vomiting, C. difficile colitis
  • Mild headache, dizziness
  • Achiles tendon rupture
  • QT prolongation and torsades de pointes (mainly moxifloxacin)
94
Q

Linezolid - MOA

A
  • protein synthesis inhibitors
95
Q

Linezolid - Resistance

A
  • Point mutations at the oxazolidinone binding site
96
Q

Linezolid - AE

A
  • Myelosuppression
  • Mitochondrial toxicity
  • Drug-drug interactions (inhibits MAO; interaction with SSRIs)
  • Bone marrow suppression and irreversible peripheral and optic neuropathy have been reported
97
Q

Rifabutin - MOA

A
  • bacterial RNA polymerase inhibitor

* works the same as rifampin

98
Q

Rifabutin - Resistance

A

• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase

99
Q

Rifabutin - Clinical Notes

A

• Rifabutin is a substrate and an inducer of cytochrome P450 enzymes

100
Q

In patients with HIV taking highly active

anti-retroviral therapy, what drug replaces Rifampin?

A

Rifabutin

101
Q

Rifabutin - AE

A
  • hepatoxicity and rash

- can also cause leukopenia, thrombocytopenia, and optic neuritis

102
Q

Rifapentine - MOA

A
  • bacterial RNA polymerase inhibitor

- works same as Rifampin

103
Q

Rifapentine - Resistance

A

• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase

104
Q

Rifapentine - Clinical Notes

A

• Potent inducer of P450 enzymes
• should not be used to treat active tuberculosis in patients with HIV infection
because of an unacceptably high relapse rate with rifampin-resistant organisms

105
Q

Rifapentine - AE

A
  • hepatoxicity and rash
106
Q

Bedaquiline - MOA

A

• Inhibits ATP synthase in mycobacteria

107
Q

Bedaquiline - Resistance

A

• Upregulation of a multi-substrate efflux pump

108
Q

Bedaquiline - AE

A
  • Nausea, arthralgia, and headache •
  • Associated with both hepatotoxicity and cardiac toxicity
  • Black box warning related to the risk of QT prolongation and associated mortality
  • Used with caution in patients with other risk factors for cardiac conduction abnormalities

CPR (22 decks)

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