Anit fungal/influenza/TB Flashcards
(108 cards)
1
Q
Amphotericin B - MOA
A
binds ergosterol, inserts pores into fungal membrane, leakage of intracellular ions causes death
2
Q
What is the cholesterol of fungi?
A
ergosterol - found in cell membrane of fungi
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
4
Q
What anti-fungal has the broadest sprectum of activity?
A
amphotericin B
5
Q
Amphotericin B - resistance
A
fungi that can alter their ergosterol, which makes it harder for the drug to bind
6
Q
Amphotericin B - PK
A
- give by IV for systemic infections
- poorly absorbed in GI (only orally given with GI infection)
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
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
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
10
Q
What can we pair flucytosine with to enhance action?
A
Amphotericin B
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
12
Q
Flucytosine - Resistance
A
• Altered metabolism of flucytosine
*Develops rapidly in flucytosine monotherapy
13
Q
Flucytosine - PK
A
- oral formulation
- widely distributed in body (even CNS - unlike amphotericin B)
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)
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
16
Q
Azoles - MOA
A
- inhibit fungal P450 enzymes –> decreased ergosterol synthesis
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
18
Q
Which three azoles can be used in aspergillus infections?
A
• Itraconazole, posaconazole, and voriconazole
19
Q
Azole - Resistance
A
- up regulation of fungal P450 enzymes –> standard dose doesn’t work
20
Q
Azole - AE
A
- minor GI problems
- liver enzyme problems
- drug interactions (due to minimal effect on human P450s)
21
Q
Ketonconazole
A
- Greater propensity to inhibit mammalian cytochrome P450 enzymes
- more common for dermatological functions
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
23
Q
What azole has reduced function when taken with Rifamycins?
A
Itraconazole
24
Q
Fluconazole
A
- high oral
- good CSF penetration
- Spectrum
• Azole- cryptococcal meningitis
- mucocutaneous
candidiasis
• No activity against Aspergillus spp. or other filamentous fungi
25
Which azole has the widest spectrum?
Fluconazole
*also has least effect on liver enzymes
26
Voriconazole
- 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.
27
Why do you have to really worry about drug interactions and doses when taking voriconazole?
it inhibits human CYP3A4
28
What azole is the tx of choice of Aspergillus? what azole has the broadest spectrum?
a. Voriconazole
| b. Posaconazole
29
Posaconazole
- 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
30
Echinocandins - MOA
* 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
31
Echinocandins - Spectrum
* Candida spp. and Aspergillus spp.
| * No coverage of C. neoformans or agents of zygomycosis / mucormycosis
32
What are the three specific echinocandins?
Caspofungin, Micafungin, and Anidulafungin
33
Caspofungin
* Disseminated and mucocutaneous candidal infections
| * Invasive aspergillosis (Not primary therapy)
34
Micafungin
* Mucocutaneous candidiasis
* Candidemia
* Prophylaxis of candidal infections in bone marrow transplant patients
35
Anidulafungin
• Esophageal candidiasis and invasive candidiasis, including candidemia
36
Echinocandin - Resistance
- point mutations in gluten synthase
37
Echinocandin - PK
- parenteral (IV)
- Half-life
a. Caspofungin: 9-11 hours
b. Micafungin: 11-15 hours
c. Anidulafungin: 24-48 hours
38
Echinocandin - AE
- minor GI effects
| - flushing
39
Neuraminidase Inhibitors - MOA
- competitive inhibitors of viral neuraminidase
- results in bunching of newly release influenza virions
- halts spread of disease within respiratory tract
40
Neuraminidase Inhibitors Class members
* Oseltamivir
* Zanamivir
* Peramivir
41
Neuraminidase Inhibitors - Spectrum
- Influenza A and B strains
42
Neuraminidase Inhibitors - Resistance
rare
43
Neuraminidase Inhibitors - PK
- early administration is key
44
Neuraminidase Inhibitors - AE
- increase risk of hallucinations, delirium, and abnormal behavior
45
Oseltamivir
* Oral administration
* Prodrug activated by hepatic esterases
* Nausea, vomiting, and headache
* Fatigue and diarrhea more common with prophylactic use
46
Zanamivir
* 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
Peramivir
* Administered as a single IV dose
* Diarrhea (most common)
* Skin or hypersensitivity reactions (less common)
48
Adamantanes class members
amantadine and rimantadine
49
Adamantanes - MOA
• 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
Adamantanes - Spectrum
Influenza A
51
Adamantanes - Resistance
- high rates in H1N1 and H3N2
52
Adamantanes - PK
- oral
53
Adamantanes - AE
* Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, and light-headedness
* Birth defects have been reported after exposure during pregnancy
!!!!
54
What drugs do you give as first line tx of TB?
* Rifampin (!!)
* Isoniazid (!!)
* Pyrazinamide (shortens tx)
* Ethambutol (more coverage)
*RIPE
55
When is Ethambutol not needed in TB tx?
when the strand is known to not be resistance to Rifampin and Isoniazid
56
Isoniazid - MOA
- inhibits Mycotic acid synthesis
| - activated by KatG
57
Isoniazid - Resistance
- 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
Isoniazid - Clinical
- oral med given daily
| - works alone in pts with latent infection
59
Isoniazid - AE
• 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
If a patient has a B6 deficiency, what drug should you be cautious to give them?
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
What is a contraindication of Isoniazid?
further use after hepatitis develops
62
Rifampin - MOA
- 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
Rifampin - Resistance
- point mutations in rpoB (gene for beta subunit)
64
Rifampin - Clinical Note
- must be administered with another anti-TB drug to prevent emergence of drug resistance
65
Rifampin - AE
* Harmless orange color to urine, sweat, and tears
* May permanently stain soft contact lenses
* Occasional adverse effects include rashes, thrombocytopenia, and nephritis
66
Ethambutol - MOA
* Inhibition of mycobacterial arabinosyl transferases
| * These are encoded by the embCAB operon
67
Ethambutol - Resistance
* 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
Ethambutol - AE
- retrobulbar neuritis (results in loss of visual acuity and red-green color blindness)
69
What is the contraindication of ethambutol?
children to young to permit assessment of visual acuity and red-green color discrimination
70
Pyrazinamide - MOA
* Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase
* Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions
71
Pyrazinamide - Resistance
- impairs uptake
| - mutations in pica that impair conversion to active form
72
Pyrazinamide - AE
- Hepatotoxicity (1-5%), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia
73
When are second line TB meds used?
* 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
Streptomycin - MOA
- protein synthesis inhibitors
75
Streptomycin - Resistance
- penetrates cells poorly
| - active against extreellular tubercle bacilli
76
Streptomycin - Clinical Notes
- can replace ethambutol
77
Streptomycin - AE
• 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
Ethionamide - MOA
- blocks synthesis of mycotic acids
| * chemically related to isoniazid
79
Ethionamide - AE
- gastric irritation
| - neurologic symptoms (relieve with B6)
80
Capreomycin - MOA
- peptide protein synthesis inhibitor
81
If a drug is resistant to streptomycin, what drug might work?
Capreomycin
82
Capreomycin - AE
* Nephrotoxic and ototoxic
| * Tinnitus, deafness, and vestibular disturbances can occur
83
Cycloserine - MOA
• 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
Cycloserine - AE
* Peripheral neuropathy and CNS dysfunction, including depression and psychoses
* headaches, tremors, and convulsions
*Pyridoxine (vitamin B6) ameliorates the neurologic toxicity
85
Aminosalicyclic Acid - MOA
• Folate synthesis inhibitor active exclusively against M. tuberculosis
86
Aminosalicyclic Acid - AE
• 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
Kanamycin/Amikacin - MOA
- protein synthesis inhibitors
88
Kanamycin/Amikacin - Resistance
amikacin has cross resistance with kanamycin
89
Kanamycin/Amikacin - Clinical Note
• Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multi-drug resistant strains
90
Kanamycin/Amikacin - AE
• Ototoxic and nephrotoxic
• Vertigo and hearing loss (most common)
- Hearing loss can be permanent
91
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - MOA
- fluoroquinolone antibiotics
| - inhibit topoisomerase II and IV
92
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - Resistance
- point mutations in DNA gyrase (aka topoisomerase II)
93
Ciprofloxacin / levofloxacin / gatifloxacin / moxifloxacin - AE
* Abdominal discomfort, nausea, vomiting, C. difficile colitis
* Mild headache, dizziness
* Achiles tendon rupture
* QT prolongation and torsades de pointes (mainly moxifloxacin)
94
Linezolid - MOA
- protein synthesis inhibitors
95
Linezolid - Resistance
- Point mutations at the oxazolidinone binding site
96
Linezolid - AE
* Myelosuppression
* Mitochondrial toxicity
* Drug-drug interactions (inhibits MAO; interaction with SSRIs)
* Bone marrow suppression and irreversible peripheral and optic neuropathy have been reported
97
Rifabutin - MOA
- bacterial RNA polymerase inhibitor
| * works the same as rifampin
98
Rifabutin - Resistance
• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase
99
Rifabutin - Clinical Notes
• Rifabutin is a substrate and an inducer of cytochrome P450 enzymes
100
In patients with HIV taking highly active
| anti-retroviral therapy, what drug replaces Rifampin?
Rifabutin
101
Rifabutin - AE
- hepatoxicity and rash
| - can also cause leukopenia, thrombocytopenia, and optic neuritis
102
Rifapentine - MOA
- bacterial RNA polymerase inhibitor
| - works same as Rifampin
103
Rifapentine - Resistance
• Point mutations in rpoB, the gene for the beta subunit of RNA polymerase
104
Rifapentine - Clinical Notes
• 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
Rifapentine - AE
- hepatoxicity and rash
106
Bedaquiline - MOA
• Inhibits ATP synthase in mycobacteria
107
Bedaquiline - Resistance
• Upregulation of a multi-substrate efflux pump
108
Bedaquiline - AE
* 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
