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Therapeutics > Dr. Kays Antifungals > Flashcards

Dr. Kays Antifungals Flashcards

1
Q

Candida spps

A
  1. C. albicans, C. glabrata, C. parapsilosis, C. krusei, C. guilliermondii, C. lusitaniae, C. auris (multi-drug resistant)
    - increased mortality if empiric anti-fungal therapy is delayed by 12 hours
    - risk factors for invasive candidiasis: prolonged stay in the ICU; central venous catheters; prolonged therapy with broad spectrum antibacterial agents; receipt of parenteral nutrition; recent surgery; HD; DM
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2
Q

Aspergillus spps

A
  1. opportunistic infection in those who are immunocompromised. A mold that is ubiquitous in the environment
  2. primarily causes disease in those who are neutropenic
  3. pulmonary system is most commonly affected but can occur anywhere
  4. definitive diagnosis requires a positive culture from a sterile site or histologic or radiologic evidence in a high-risk patient with negative cultures
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3
Q

cryptococcus neoformans

A
  1. opportunistic and pathogenic
  2. encapsulated yeast that primarily affects the CNS and respiratory tract
  3. more common in patients who are infected with HIV, who received organ transplants, or high dose corticosteroids
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4
Q

Zygomycetes

A
  1. pathogens: Rhizopus, Absidia, Mucor
  2. most common infections: pulmonary system; paranasal sinuses with extension to the brain
  3. primary risk factors: DM, immunosuppression (with profound neutropenia), penetrating injuries from natural disasters or combat
  4. definitive diagnosis: tissue invasion on histopathologic exam with or without microbiologic evidence
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5
Q

Endemic (pathogenic) fungi

A
  1. histoplasma capsulatum, blastomyces spp, coccidioides immitis
  2. may cause disseminated disease via primary pulmonary infection
  3. may cause disease in normal host; higher risk in patients with suppressed cell-mediated immunity (HIV/AIDs, high-dose corticosteroid, TNF-alpha inhibitor therapy, transplant)
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6
Q

Histoplasma capsulatum

A

midwestern states along ohio and mississippi river valleys; exposure to bat guano or other large birds; demolition or construction

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7
Q

Blastomyces spps

A

southeastern and midwestern states along Ohio and Mississippi river valleys and great lakes region

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8
Q

Coccidioides immitis/posadasii

A

cluster in southwestern united states (southern arizona, southern california, southwest new mexico, west texas)

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9
Q

Amphotericin B

A
  1. binds to ergosterol and gets inserted into the fungal cytoplasmic membrane -> disruption of the fungal cytoplasmic membrane -> increased cell permeability -> leakage of sodium/potassium/cellular constituents, loss of membrane potential, metabolic disruption -> cell death.
    - at low conc. K+ channel activity is increase and at high conc pores are formed
  2. fungicidial -> peak/mic
  3. resistance - decreased ergosterol biosynthesis, synthesis of alternative sterols
  4. rapidly and widely distributed into tissue; poor penetration into the CSF, even if meninges are inflamed
  5. renal and hepatic impairment and HD do not affect drug clearance
  6. dosed based in ideal body weight or adjusted body weight
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10
Q

amphotericin B SOA

A
  1. candida spp (not C. lusitaniae)
  2. Cryptococcus neoformans (DOC in combination for cytopococcus menigititis)
  3. blastomyces dermatitidis
  4. histoplasma capsulatum (DOC in disseminated histoplasmosis in immunocrompromised hosts)
  5. coccidioides immitis
  6. aspergillus spp (reduce activity against A. terreus)
  7. mucor spps (and other zygomycetes)
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11
Q

amphotericin B clinical uses

A
  1. dissemenated candidiasis
  2. cryptococcosis
  3. aspergillosis
  4. histoplasmosis
  5. blastomycosis
  6. coccidioidomycosis
  7. mucormycosis
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12
Q

amphotericin B ADRs

A
  1. infusion-related: headache, fever, chills, arthralgias, myalgias, nausea, vomiting, tachypnea, hypotension
    - pretreat with Tylenol, or aspirin, antihistamines, meperidine, phenothiazines. Hydrocortisone can be added to the infusion container
  2. thrombophlebitis
    - slow infusion (4-6 hours): rotate infusion sites, in-line filters (>0.22 micron). Heparin may be added to the infusion container
  3. nephrotoxicity - dose-dependent increase in SCr and BUN
    - sodium repletion with 0.5-1 L of NS before and after completion of infusion
  4. hypokalemia (rapid infusion in patients with renal insufficiency can lead to hypokalemia and ventricular fibrillation)
  5. hypomagnesium
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13
Q

amphotericin B drug interactions

A
  1. nephrotoxic agents - potentiation of nephrotoxicity
  2. digoxin and skeletal muscle relaxants - potentiation secondary to hypokalemia
  3. flucytosine - increase therapeutic effect; potential for increased toxicity
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14
Q

Flucytosine (Ancobon)

A
  1. 5-FC -> enters fungal cell -> deaminated to 5-FU -> 5-FU gets incorporated into fungal RNA -> interference with protein synthesis.
  2. 5-FC enters fungal cell -> metabolized to 5-FdUMP monophosphate -> inhibits thymidylate synthetase -> interferes with DNA synthesis
  3. SOA: cryptococcus neoformans, candida spps
  4. penetrates in CSF regardless of inflammation of meninges
  5. removed by HD and PD
  6. primarily used in combination with amphotericin B for cryptococcal meningitis
  7. ADR: GI (N/V/D, abdominal pain) and bone marrow suppression (more common with serum concentrations >100 mcg/mL)
  8. dose based on ideal body weight (if non-severe) or adjusted body weight (if severe)
  9. monitoring:
    - baseline: CBC, platelets, SCr, BUN
    - reduce dose in patients with bone marrow or GI toxicity
    - TDM: goal peak conc 70-80 mcg/mL
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15
Q

Azoles

A

inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P450 dependent enzyme lanosterol 14-alpha-demethylase.
Blocks formation of ergosterol -> damage to fungal cell membrane -> disruption of structural integrity -> leakage of cytoplasm -> inhibition of growth (fungistatic)

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16
Q

Ketocoazole SOA

A
  1. Candida Albicans
  2. Cryptococcus Neoformans
  3. Histoplasma Capsulatum
  4. Dermatophytes
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17
Q

Ketoconazole

A
  • absorption is inversely related to gastric pH (affected by gastric pH)
  • widely distributed throughout the body
  • extensively metabolized in the liver.
  • dosing adjustment is not needed in renal failure; not removed by HD or PD
  • hepatotoxicity
  • endocrine: dose-dependent inhibition of adrenal steroid ad testosterone synthesis -> gynecomastia, decreased libido, oligospermia, loss of hair, and menstrual irregularities
  • a very potent inhibitor of CYP3A4
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18
Q

Drug interactions with CYP3A4 and ketoconazole

A
  1. drugs affecting gastric pH-increase pH, decrease bioavailability
  2. anticoagulants - prolonged PT
  3. rifampin - decrease ketoconazole concentrations
  4. cyclosporine, tacrolimus, sirolimus - increased concentrations
  5. phenytoin - decreased clearance, increased concentrations
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19
Q

Itraconazole (Sporanox; SUBA-itraconazole (Tolsura))

A
  1. absorption dependent on gastric acidity. Oral solution is better absorbed in fasting state and is not affected by gastric acidity.
  2. SUBA-itraconazole absorption is not affected by gastric acidity and may be given with or without food (recommended to give with food).
  3. widely distributed throughout the body
  4. metabolized predominantly by CYP450 3A4 isoenzyme. -> CYP3A4 potent inhibitor
  5. Active metabolite - hydroxyitraconazole
  6. no dosage adjustment for renal dysfunction and not removed by HD or PD
  7. TDM: serum trough concentrations >0.5-1 mcg/mL associated with efficacy. >3 associated with increased adverse events
20
Q

itraconazole clinical uses

A
  1. histoplasmosis (first choice)
  2. aspergillosis
  3. blastomycosis
  4. life-threatening infections
  5. onychomycosis of toenails and fingernails
21
Q

itraconazole SOA

A
  1. aspergillus spp
  2. histoplasma capsulatum (DOC in non-immunocompromised patient)
  3. blastomyces dermatitidis
  4. candida spps
  5. coccidioides immitis
  6. cryptococcus neoformans
  7. sporothrix schenckii
22
Q

itraconazole ADRs

A
  1. hepatotoxicity
  2. CHF (boxed warning) - contraindicated in patients with ventricular CHF or history of CHF
  3. QTc prolongation
23
Q

Fluconazole (Diflucan)

A
  1. well absorbed orally independent of gastric acidity; may be administered without regard to food.
  2. concentration in the CSF - 60% of serum with uninflamed meninges; 80% of serum with inflamed meninges
  3. excreted unchanged in urine - dosage reduction required in renal insufficiency
  4. HD reduces serum conc 50%
  5. doses should be based on total body weight
  6. potent inhibitor of CYP2C9 and moderate inhibitor CYP3A4
  7. ADRs: QTc prolongation -torsades de pointes and elevation of hepatic transaminases
24
Q

fluconazole SOA

A
  1. candida spp (less active vs C. glabrata; not active vs C. krusei)
  2. cryptococcus neoformans (DOC for meningitis for the first 2 weeks)
  3. histoplasma capsulatum
  4. blastomyces dermatitidis
  5. Coccidioides immitis
25
Q

fluconazole clinical indications

A
  1. non-invasive candidiasis: oropharyngeal, esophageal, vaginal
  2. invasive candidiasis (candidemia)
  3. prophylaxis in patients undergoing bone marrow transplant
  4. candida UTI
  5. cryptococcal meningitis
    - inferior alternative for induction therapy
    - consolidation therapy for 10-12 weeks after CSF neg
    - maintenance therapy for at least 1 year and remains asymptomatic from cryptocococcal infection AND CD4 count >/= 100 cells >/= 3 months and suppressed HIV RNA in response to effective antiretroviral therapy
26
Q

Voriconazole (Vfend)

A
  1. oral bioavailability is not affected by H2 antagonists, PPI, antacids. Tablets and oral suspension should be taken 1 hour before or after meals
  2. extensive tissue distribution
  3. significantly metabolized by cytochrome P450 isoenzyme (2C19, 2C9, 3A4). 2C19 genetic polymorphism - poor metabolizers 4-fold higher AUC
  4. metabolism is saturable - PK are non-linear
  5. No difference in Cmax and AUC in mild to severe renal dysfunction. NO dosage adjustment necessary for ORAL dosing. AVOID IV VORICONAZOLE IF CRCL <50 ML/MIN
  6. patients with CRCL 30-50 ML/MIN - accumulation of the intravenous vehicle SBECD
  7. oral and IV maintenance doses do not produce the same voriconazole exposure
  8. adults weighing <40 kg should receive half the oral maintenance dose
  9. oral maintenance dose should be decreased by 50% in mild-moderate hepatic cirrhosis
  10. dosing should be based on ideal body weight or adjusted body weight
27
Q

Voriconazole SOA

A
  1. aspergillus spp (including amphotericin and itraconazole-resistant strains)
  2. Scedosporium apiospermum
  3. candida spp (C. albicans, C. tropicalis, C. glabrata, C. parapsilosis, C. krusei)
  4. histoplasma capsulatum
  5. Blastomyces dermatitidis
  6. cryptococcus neoformans
  7. fusarium spps
28
Q

Voriconazole clinical uses

A
  1. invasive aspergillosis
  2. candidemia in non-neutropenic patients and other deep tissue candida infections
  3. esophageal candidiasis
  4. scedosporiosis and fusariosis
29
Q

Voriconazole ADRs

A
  1. visual disturbances - blurred vision, colo changes, photophobia, photopsia, hallucinations
  2. elevated LFTs
  3. QTc prolongations
  4. CNS
  5. peripheral neuropathy
  6. phototoxic skin reactions- may progress to squamous cell carcinoma (long term treatment)
  7. diffuse, painful periostitis secondary to excess fluoride
30
Q

Drug interactions (CYP3A4, CYP2C9, CYP2C19) with voriconazole

A
  1. effect of other drugs on voriconazole - rifampin, rifabutin, carbamazepine (potent CYP450 inducer) - co-administration contraindicated
  2. effect of voriconazole on other drugs:
    - increased exposure due to inhibition of metabolism: sirolimus, terfenadine, astemizole, cisapride, pimozide, quinidine - contraindicated
    - cyclosporine, tacrolimus, warfarin, statins, benzos, CCBs, sulfonylureas, vinca alkaloids - careful monitoring and dosage adjustment
    - protease inhibitors
31
Q

Posaconazole SOA

A
  1. candida spps (less active against C. glabrata)
  2. Aspergillus spps
  3. cryptococcus neoformans
  4. histoplasma capsulatum
  5. mucor spps
  6. coccidioids spps
32
Q

Posazonazole (Noxafil)

A
  1. oral suspension absorption affected by gastric pH (decreased absorption with PPIs)
  2. suspension and tablets better absorbed with food
  3. metabolized by glucuronidation NOT CYP450
  4. IV formulation contains cyclodextrin - AVOID if CRCL <50 mL/min
  5. TDM: trough conc >1 mcg/mL associated with treatment response for invasive aspergillos. <0.7 mcg/mL associated with breakthrough fungal infections
  6. Strong inhibitor of CYP3A4
  7. clinical uses: prophylaxis of invasive aspergillus and candida infections in immunocompromised pts, oropharyngeal candidiasis and refractory to fluconazole and/or itraconazole, may be used as salvage therapy for tx of aspergillosis or mucor infections
  8. ADRs: elevated LFTs, bilirubin, hypokalemia, QTc prolongation, rash
33
Q

Isavuconazole (Cresemba)

A
  1. isavuconazonium sulfate is the prodrug of isavuconazole - metabolized by esterases in the blood
  2. Linear PK
    - may be administered orally with or without food
    - very large Vd
    - highly protein-bound
  3. renal excretion <1% - NO DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT OR ESRD
  4. IV formulation does NOT contain cyclodextrin
  5. Not removed by HD
  6. no dosage adjustment in mild or moderate hepatic impairment
  7. clinical uses: invasive aspergillosis in patients > 18 YOA and invasive mucormycosis in patients > 18 YOA
  8. IV formulation must be administered through in-filter and oral capsules should be swallowed whole - do not chew, crush, dissolve, or open the capsules.
34
Q

Isavuconazole SOA

A
  1. aspergillus spps (A. flavus, A. fumigatus, A. niger)
  2. Mucor
  3. Rhizopus
35
Q

Isavuconazole ADRs

A
  1. N/V/D and headache
  2. increased LFTs - evaluate LFTS at the beginning of treatment and throughout treatment
  3. infusion-related reactions 9hypotension, dyspnea, chills, dizziness, paresthesias, hypoesthesia) - discontinue if occurs
  4. hypokalemia
  5. hypersensitivity and severe skin reactions (SJS)
  6. DOES NOT CAUSE QT PROLONGATION
36
Q

Isavuconazole drug interactions

A
  1. isavuconazole is a substrate for CYP3A4, a moderate inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and mild inhibitor of P-gp
  2. CYP3A4 inhibitors/inducers
  3. CYP3A4 substrates - isavuconazole increases concentrations of cyclosporine, tacrolimus, sirolimus, midazolam.
  4. P-gp substrate (digoxin)
37
Q

Isavuconazole contraindications

A
  1. co-administration with strong CYP3A4 inhibitors (ketoconazole, high-dose ritinovir) -> significant increase in plasma isavuconazole concentration
  2. co-administration with strong CYP3A4 inducers (rifampin, carbamazepine, St. John’s wort, long-acting barbituates) -> significantly decrease plasma isavuconazole concentrations
  3. patients with familial short QT syndrome - isavuconazole shortens QT interval
38
Q

Echinocandin anti-fungal agents

A
  1. Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxis)
  2. glucan synthesis inhibitor leading to non-competitive inhibition 1,3-beta-D-glucan, an integral polysaccharide component of the fungal cell wall (fungicidal)
  3. glucan synthesis occurs on the cytoplasmic side of the fungal cell membrane forming linear glucan fibrils that extrude into periplasmic space for incorporation into the fungal cell wall
  4. glucan fibrils covalently bind to chitin forming a rigid structure responsible for the cell wall strength and shape - important in maintaining the osmotic integrity of the fungal cell wall.
  5. 2 genes FKS1 and FKS2 encode for glucan synthase expression -> mutations confer cross-resistance to all echinocandins
39
Q

Echinocandin SOA

A
  1. aspergillus spp
  2. candida spps, including azole-resistant strains
  3. limited activity against histoplasma capsulatum, cryptococcus neoformans, fusarium, and mucor
40
Q

Capsofungin (Cancidas)

A
  1. slowly metabolized by hydrolysis and N-acetylation
  2. no dosage adjustment for renal insufficiency or mild hepatic impairment
  3. Not removed by HD
  4. clinical uses:
    - candidemia, esophageal candidiasis, empiric therapy of presumed fungal infections in febrile neutropenia, invasive aspergillosis in patients who are refractory to or intolerant to other therapies
  5. reduce daily dose in severe hepatic dysfunction
  6. Drug interactions:
    - does not induce or inhibit CYP450 system; poor substrate for CYP450
    - tacrolimus, cyclosporine, ART’s
  7. ADRs:
    - histamine-mediated symptoms: rash, facial swelling, pruritus, flushing
    - fever
    - phlebitis
    - N/V/HA
    - increased LFTs, decreased K+, eosinophilia, increased urine protein and RBCs, decreased Hgb/Hct
41
Q

Micafugin (mycamine)

A
  1. metabolized by the liver - no dosage adjustment for renal dysfunction
  2. clinical uses: oropharyngeal and esophageal candidiasis, candidemia, aspergillosis, prophylaxis of candida infections in HSCT
  3. not metabolized via CYP450 pathways
  4. ADRs: hyperbilirubinemia, N/D, eosinophilia, rash, pruritus, urticarial
42
Q

Anidulafungin (Eraxis)

A
  1. long half-life 26.5 hours in patients with fungal infections
  2. not metabolized or really eliminated -> undergoes slow chemical degradation
  3. no dosage adjustments are required for renal or hepatic dysfunction
  4. clinical uses: candidemia and other candida infections (peritonitis, intra-abdominal abscess), esophageal candidiasis (significantly higher release rate than fluconazole)
  5. not a substrate inducers, or inhibitor of CYP450
  6. ADRs: histamine mediate symptoms, diarrhea, increased LFTs, hypokalemia
43
Q

Ibrexafungerp (Brexafemme)

A
  1. inhibits 1,3-beta-D-glucan synthase
  2. limited cross-resistance with echinocandins due to only partial overlap of binding sites
  3. bioavailability dependent on gastric acid
  4. may be taken with or without food but better absorbed with food
  5. excellent penetration into deep tissues (except CNS)
  6. elimination primarily biliary and hepatic metabolism
  7. ADRs: N/V/D, abdominal pain, dizziness, does not cause QT prolongation
  8. metabolized by and a weak inhibitor of CYP3A4; weak inhibitor of CYP2C8
    - in strong CYP3A4 inhibitors reduce the dose
    - in strong or moderate CYP3A4 inducers avoid concomitant inducers
44
Q

Ibrexafungerp SOA

A
  1. candida spps, including azole and echinocandin resistant C. albicans and C. glabrata harboring FKS mutations, C, parasilosis, C. auris
  2. aspergillus spps - similar activity to echinocandins (fungistatic)
  3. pneumocystis jiroveci
  4. not active in mucor, fusarium, cryptococcus, or endemic fungi
45
Q

ibrexafungerp clinical uses

A
  1. VVC in adult and post–menarchal pediatric females
    - verify pregnancy status prior to initiating treatment (CONTRAINDICATED in pregnancy - use effective contraception during and for 4 days after treatment

Therapeutics (11 decks)

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