Kays Antifungal Agents Lecture 1 Flashcards
What are the common Candida species
C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. guilliermondii, C.
lusitaniae, C. auris (multidrug-resistant)
Invasive candidiasis refers to
to severe forms of the disease (not oropharyngeal or
esophageal candidiasis or uncomplicated candiduria
Risk factors for invasive candidiasis:
prolonged stay in ICU; central venous catheters;
prolonged therapy with broad spectrum antibacterial agents; receipt of parenteral
nutrition; recent surgery (especially abdominal); hemodialysis; diabetes mellitus
Aspergillus species is what type of species
mold that is ubiquitous in the environment
Aspergilluses causes infections primarily in
immunocompromised hosts (neutropenia) and it is difficult to treat
Cryptococcus neoformans is an
Encapsulated yeast that primarily affects the CNS and respiratory tract
Cryptococcus neoformans is most common in patients with
HIV, who have received organ
transplants, or high-dose corticosteroid
Zygomycetes pathogen types are
Rhizopus, Absidia, Mucor
Zygomycetes infections are common in what areas of the body
pulmonary system; paranasal sinuses with extension to the brain
Primary risk factors for Zygomycetes are:
diabetes mellitus
immunosuppression (with profound neutropenia)
penetrating injuries from natural disasters (tornadoes, hurricanes, volcanic eruptions) or combat
Histoplasma capsulatum is most common in what area of the united States
Midwestern states along Ohio and Mississippi river
valleys; exposure to bat guano (cave exploration) or other large birds; demolition or
construction
Blastomyces species is most common in whats area of the united states
Southeastern and Midwestern states along Ohio and
Mississippi river valleys and Great Lakes region
Coccidioides immitis/posadasii is most common in what area of the United States
cluster in southwestern United States (southern
Arizona, southern California, southwest New Mexico, west Texas)
Ampotericin B MOA
Increases membrane permeability of fungal cells by binding to ergosterol and causes leakiness and loss of membrane potential
Amphotericin B Resistance MOA & Pharmacodynamic monitoring parameter
- decreased ergosterol biosynthesis, synthesis of alternative sterols.
Monitoring Parameters is Peak to MIC ratio
Amphotericin B Spectrum of activity
- Candida species (not C. lusitaniae)
- Cryptococcus neoformans
- Blastomyces dermatitidis
- Histoplasma capsulatum
- Coccidioides immitis
- Aspergillus species (reduced activity against A. terreus)
- Mucor species (and other zygomycetes)
Deoxycholate distribution ) used with amphotericine
Poor penetration into CSF, even if meninges are inflamed (»3% of serum)
Highly protein bound (> 90%) – mainly to b-lipoproteins
not appreciably metabolized
Deoxycholate elimination
Tri-exponential elimination. 1/2 life 24-48 hours and terminal elimination in 15 days. Renal and Hepatic impairment do not affect clearance
Lipid associated formulations of amphotericin B an kidney concentrations
80-90% reduction of concentrations in the kidneys
Clinical Uses of Deoxycholate
- Disseminated candidiasis
- Cryptococcosis
- Aspergillosis
- Histoplasmosis
- Blastomycosis
- Coccidioidomycosis
- Mucormycosis
Deoxycholate Dosing and Administration
0.1mg/kg or 1kg over 20 to 30 minutes (do not premedicate.
Infused over 4-6 hours (rapid infusions associated with more adverse reactions.
Intrathecal/ intraventricular administration: 0.1mg then increase to a maximum o f0.5 every 48-72 Hours
L-AmB dosing
1.5-6mg/kg daily infused over 2 hours
ABLC Dosing
5mg/kg dosing daily, infused at 2.5mg/kg/hour
Dosing Weight for Amphotericin B
Use Ideal or adjusted despite lipophilicity
Deoxycholate infusion related Adverse reactions
- Infusion related (pretreat with NSAID, antihistamine etc)
- Thrombophlebitis: slow infusion and rotate sites, consider adding heparin
Deoxycholate Non-infusion related adverse reactions
- Dose dependent nephrotoxicity (increases in serum creatinine and BUN) can consider sodium repletion in depleted patients. use saline both before and after AMB
- Hypokalemia, Hypomagnesemia, Bicarb wasting, anemia
Intrathecal Deoxycholate administration adverse effects
nerve pain, head ache, vomiting, paraplegia, seizures,
Lipid associated formulations of amphotericin B an there adverse effects
Less nephrotoxicity & infusion-related toxicities with lipid-associated formulations except for ABCD.
- manage L-AMB infusion reactions with diphenhydramine
Interactions for Amphotericin B
- Nephrotoxic agents
- Digoxin and skeletal muscle relaxants, may potentiate hypokalemia
- Flucytosine - increase therapeutic effect and increase potential toxicity
FLUCYTOSINE Mechanism of Action
- 5-FC enters fungal cell –> deaminated to 5-FU –> 5-FU gets incorporated into fungal
RNA –> interference with protein synthesis - 5-FC enters fungal cell –> metabolized to 5-fluorodeoxyuridine monophosphate –>
inhibits thymidylate synthetase –> interferes with DNA synthesis
FLUCYTOSINE Spectrum of activity
- Cryptococcus neoformans
2. Candida species
FLUCYTOSINE PK
- Absorption – well absorbed orally (> 90%
- Distribution
a. Penetrates into CSF ( »75% of serum)
b. Negligible protein binding (2 to 4%) - Metabolism/Excretion
a. Small amount converted to 5-FU
b. 85 to 95% excreted unchanged in urine
c. Normal half-life – 3 to 5 hours; anephric half-life – 85 hours
d. Removed by HD & PD
Flucytosine clinical use
primarily in combination with amphotericin B for cryptococcal meningitis
Flucytosine Adverse reactions
- Gastrointestinal (6%) – nausea, vomiting, diarrhea, abdominal pain, enterocolitis
- Hematologic – Bone marrow suppression (more common with serum concentrations > 100 μg/ml)
Flucytosine Dosing
Normal Renal Function – 100 to 150 mg/kg/DAY PO in 4 divided doses (25 to 37.5 mg/kg/DOSE Q6H) – available in 250 mg and 500 mg capsules.
Renal Dosing
see chart start at 25-37.5 when greater than 40 q 6 hours
Dosing body weight for Flucytosine
ideal body weightfor non-severe
adjusted body weight if severe
Flucytosine Monitoring
a. Baseline: CBC, platelets, Scr, BUN
b. Reduce dose in patients with bone marrow or GI toxicity
Ketoconazole MOA
- inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P-450 dependent
enzyme lanosterol 14-α-demethylase - Blocks formation of ergosterol → damage to fungal cell membrane –> disruption of
structural integrity –> leakage of cytoplasm –> inhibition of growth (fungistatic)
Ketoconazole Spectrum of Activity
- Candida albicans
- Cryptococcus neoformans
- Histoplasma capsulatum
- Dermatophytes (tinea
Ketoconazole PK
Absorption
a. Well absorbed orally (F=75%); peak concentration 1 to 2 hours after oral dosing
b. Absorption is inversely related to gastric pH
Distribution
a. Widely distributed throughout body (CSF penetration is negligible)
b. Protein binding 95 to 99%
Metabolism/Elimination
a. Extensively metabolized in the liver
b. Major excretory route is enterohepatic – 85 to 90% excreted in bile & feces
c. Biphasic elimination – half-life 2 hours (during the first 8-12 hours); 9 hours
thereafter
d. Dosage adjustment not needed in renal failure; not removed by HD or PD
Ketoconazole Clinical Uses
- not used orally for first line therapy due to toxicity
- chronic mucocutaneous candidiasis
- histoplasmosis in immunocompetent hosts
Ketoconazole Adverse Reactions
- Gastrointestinal (20-30%) – N/V/D; anorexia; abdominal pain
- Hepatotoxicity
- Endocrine - dose dependent inhibition of adrenal steroid and test synthesis, menstrual irregularties
Ketoconazole Drug interactions
CYP3A4 inhibitor
Prolonged PT in anticoagulants
Rifampin decreases ketoconazole conc
Cyclosporinw, tacrolimus, sirolimus increased concentrations
Phenytoin decreased clearance and increased conc
Itraconazole MOA
- Inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P-450 dependent
enzyme lanosterol 14-α-demethylase - Blocks formation of ergosterol → damage to fungal cell membrane –> disruption of
structural integrity –> leakage of cytoplasm –> inhibition of growth (fungistatic)
Itraconazole spectrum of activity
- Aspergillus spp.
- Histoplasma capsulatum
- Blastomyces dermatitidis
- Candida species
- Coccidioides immitis
- Cryptococcus neoformans
- Sporothrix schenckii
Itraconazole PK
Absorption
- after oral administration is dependent on GI acidity. oral solution better absorbed than capsules (not acid dependent. SUB-itraconazole is very bioavvailable and not acid dependent
Distribution
- widely distributed throughout body tissues poor CNS
Metabolism/Elimination
- CYP3A4 predominantly. long half-life 30-40 hours. clearance decreases with higher doses, no adjustment for renal dysfunction
Itraconazole Clinical Uses/Dosing
- Histoplasmosis (first choice) – 200 mg PO TID x 3 days, then 200 mg PO BID
- Aspergillosis (not first-line) – 200 mg PO BID
- Blastomycosis – 200 mg PO TID x 3 days, then 200 mg PO BID
- Life-threatening infections – administer oral loading dose of 200 mg three times daily
for first 3 days of therapy, then 200 mg PO daily or BID - Onychomycosis of toenails – 200 mg PO daily for 12 consecutive weeks
- Onychomycosis of fingernails – 200 mg PO BID for 1 week; repeat 3 weeks later
Itraconazole drug monitoring
Serum trough conc 0.5-1 microgram/ml associated with efficacy
Itraconazole Adverse Reactions
Hepatotoxicity, CHF, QTC, amd Pregnant and nursing mothers
Itraconazole Drug interactions
metabolized by CYP3A4
- increased drug concentrations if administered with itraconazoledigozxin, quinidine, benzidiazapines, HMG-CoA reductase inhibtors
- decreased plasma concentrations with carbamazepine, phenytoin, phenobarbital, rifampin, fiabutin, nevirapine
- increased Itraconazole conc. clarithromycin, ininavir, and ritonavir
Fluconazole MOA
- Inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P-450 dependent
enzyme lanosterol 14-α-demethylase - Blocks formation of ergosterol → damage to fungal cell membrane ® disruption of
structural integrity ® leakage of cytoplasm ® inhibition of growth (fungistatic)
Fluconazole Spectrum of activity
- Candida species (less active vs. C. glabrata [up to 30% resistance]; not active vs. C. krusei)
- C. albicans resistance reported (2.1-5.7%)
- Cryptococcus neoformans
- Histoplasma capsulatum
- Blastomyces dermatitidis
- Coccidioides immitis
Fluconazole PK
Absorption - good orally Distribution - 60% serum in uninflammed meninges Metabolism/Excretion - unchanged in urine, long half life (30 hours) - reduction required in renal insufficncy - removed by dialysis
Fluconazole Clinical Uses and Dosing
- Noninvasive candidiasis
a. Oropharyngeal – 200 mg on day 1, then 100-200 mg daily for 2 weeks
b. Esophageal – 400 mg on day 1, then 200-400 mg daily for 14-21 days
c. Vaginal – 150 mg x 1 dose - Invasive candidiasis (e.g., candidemia) – if C. albicans: 800 mg (12 mg/kg) loading
dose, then 400 mg (6 mg/kg) daily; if C. glabrata: 800 mg daily (loading dose?)
-Prophylaxis in patients undergoing bone marrow transplantation – 400 mg daily - Cryptococcal Meningitis - inferior alternative to amphotericin B w/ or w/o flucytosine for induction therapy
What Body weight should be used for Fluconazole Dosing
TBW
Fluconazole Adverse Reactions
QT prolongation, torsades de point
Flucconazole Drug Interactions
Potent inhibitory of CTP2C9
Moderate inhibitor of CYP3A4
Voricaonazole MOA
- Inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P-450 dependent
enzyme lanosterol 14-α-demethylase - Blocks formation of ergosterol → damage to fungal cell membrane ® disruption of
structural integrity ® leakage of cytoplasm ® inhibition of growth (fungistatic)
Voriconazole SOA
- Aspergillus species (including amphotericin and itraconazole-resistant strains
- Scedosporium apiospermum
- Candida species (C. albicans, C. tropicalis, C. glabrata, C. parapsilosis. C. krusei)
- C. glabrata resistance (0.1-18.4%)
- Histoplasma capsulatum
- Blastomyces dermatitidis
- Cryptococcus neoformans
- Fusarium species
Voriconazole PK
Absorption
- orally available, tablets taken 1 hour before or after meals
Distribution
- Extensive tissue binding
Metabolism
- Significantly metabolized by cytochrome P450 isoenzymes (2C19, 2C9, 3A4)
- Metabolism is saturable – pharmacokinetics are non-linear
Elimination
- half life 6 hours
- no dosage adjustment for oral dosing
- do not use IV Voriconazole if CRCL <50 (see dosing chart in notes)
Voriconazole Adverse Events
- Visual Disturbances
- Elevated Liver function tests
- QTc prolongation
- skin reactions
- CNS
Voriconazole TDM
trough concentrations goals 1-1.5micro/ml
Voriconazole Drug Interaction (CYP3A4, CYP2C9, CYP2C19)
- Rifampin, rifabutin, carbamazepine will decrease voriconazole levels
- increased exposure to voriconazole with (sirolimus, terfenadine, astermizole, contraindicated)
Posaconazole MOA
blocks synthesis of ergosterol – same as other triazole agents
Posaconazole SOA
- Candida species (less active against C. glabrata)
- Aspergillus species
- Cryptococcus neoformans
- Histoplasma capsulatum
- Mucor species
- Coccidioides species
Posaconazole PK
- Oral suspension: decreased absorption with PPI use
- DR tablets: absorption not affected
- Suspension absorption better with food
- protein bound and primarily excreted with feces
- avoid when Cr. Cl is < 50
Posaconazole Clinical Use
- Prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients (HSCT; hematologic malignancies with prolonged neutropenia) - Oropharyngeal candidiasis - Oropharyngeal candidiasis refractory to fluconazole and/or itraconazole -
Posaconazole TDM
- trough concentrations < 0.7 associated with fungal breakthrough for prophylaxis
- trough concentrations > 1 assosciated with treatment response for invasive aspergillus
Posaconazole Drug Interaction (strong CYP3A4 inhibitor)
Cyclosporine, Tacrolimus, Sirolimus, Midazolam
Posaconazole Adverse Events
N/V, Elevated Liver enzymes, QTC prolongation
Isavuconazole MOA
Isavuconazonium sulfate is the prodrug of isavuconazole – metabolized by esterases in
blood
2. Inhibits synthesis of ergosterol (key component of fungal cell membrane) by inhibiting lanosterol 14-alpha-demethylase (responsible for conversion of lanosterol to ergosterol)
–> depletion of ergosterol weakens cell membrane structure and function
Isavuconazole SOA
- Aspergillus species (A. flavus, A, fumigatus, A. niger)
- Mucor
- Rhizopus
Isavuconazole PK
Linear PK up to 600mg ,
good oral bioavailability High VD. no dosage adjustment for renal impairment or ESRD.
Isavuconazole Clinical Uses
- Invasive aspergillosis in patients ≥ 18 years of age
2. Invasive mucormycosis in patients ≥ 18 years of age
Isavuconazole Adverse Events
N/V , infusion related reactions, Hypokalemia, Hypersensitivity, does not cause QTc prolongation
Isavuconazole Drug Interactions (CYP3A4 substrate)
- agent increases concetrations of cyclosporine, tacrolimus, sirolimus, midazolam
Isavuconazole Contraindications
ketoconazole, ritonavir, rifampin, carbamazepine, st johns wart, do not use in patients with familial short QTc syndrome
Caspofungin MOA
Glucan synthesis inhibitor leading to noncompetitive inhibition 1,3-β-D-glucan, an
integral polysaccharide component of fungal cell wall ® fungicidal
Caspofungin SOA
- Aspergillus species
- Candida species, including azole-resistant strains (C. glabrata resistance up to 12%;
may have activity vs. C. auris) - Less active vs. C. parapsilosis
- Limited activity against Histoplasma capsulatum, Cryptococcus neoformans,
Fusarium, and Mucor
Caspofungin PK
IV only, polyphasic half-life, 9-11 hours, then 40 to 50, no dosage adjustment in renal or mild hepatic issues.
Caspofungin Indications
- 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
Caspofungin Drug Interactions
- Does not induce or inhibit CYP450 system, poor substrate
- decreases tacrolimus AUC
- Cyclosporine increases caspofungin
Caspofungin Adverse Drug reactions
- Histamine mediated symptoms
- Fever
- Phlebitis at infusion sites
Micafungin MOA
Glucan synthesis inhibitor leading to noncompetitive inhibition 1,3-β-D-glucan, an
integral polysaccharide component of fungal cell wall ® fungicidal
Micafungin SOA
- Aspergillus species
- Candida species, including azole-resistant strains (C. glabrata resistance up to 12%;
may have activity vs. C. auris) - Less active vs. C. parapsilosis
- Limited activity against Histoplasma capsulatum, Cryptococcus neoformans,
Fusarium, and Mucor
Micafungin PK
IV, half-life 14-17 hours, metabolized by liver and not needing renal adjustment
Micafungin Clinical Uses
- Oropharyngeal and esophageal candidaiasis
- Candidemia
- Aspergillosis
- Prophylaxis of Candida infections
- Dosing in obesity (dosing as body weight +42. up to 200 mg round to 25 mg
Micafungin Drug Interactions
- not metabolized via CYP450 pathways
Micafungin Adverse Events
Byperbilirubinemia, Eosinophelia, rash pruritic
ANIDULAFUNGIN MOA
Glucan synthesis inhibitor leading to noncompetitive inhibition 1,3-β-D-glucan, an
integral polysaccharide component of fungal cell wall ® fungicidal
ANIDULAFUNGIN SOA
- Aspergillus species
- Candida species, including azole-resistant strains (C. glabrata resistance up to 12%;
may have activity vs. C. auris) - Less active vs. C. parapsilosis
- Limited activity against Histoplasma capsulatum, Cryptococcus neoformans,
Fusarium, and Mucor
ANIDULAFUNGIN PK
IV, long half-life 26.5 hours, no renal or hepatic metabolism
ANIDULAFUNGIN Clinical Uses
- Candidemia and other Candida infections
- Esophageal candidiasis
- Higher relapse rate than fluconazole
ANIDULAFUNGIN Drug Interaction
virtually none
Andidulafungin Adverse Events
Histamine mediated symptoms Hypokalemia
IBREXAFUNGERP MOA
- Similar to the echinocandins (structurally different)
- Limited cross resistance with echinocandins due to only partial overlap of binding sites
IBREXAFUNGERP SOA
- Candida species, including azole- and echinocandin-resistant C. albicans and C.
glabrata harboring FKS mutations, C. parapsilosis, C. auris - Aspergillus species – similar activity to echinocandins; fungistatic
- Pneumocystis jiroveci
- Not active Mucor, Fusarium, Cryptococcus, or endemic fungi
IBREXAFUNGERP PK
- available orally, dependent on gastric acid, better absorbed with food.
- large VD
- Deep tissue penetration except for CNS
Ibrexafungerp Clinica Uses
- Vulvovaginal candidiasis (VVC) in adult and post-menarchal pediatric females
- Verify pregnancy status prior to initiating treatment
Ibrexafungerp Adverse Reactions
Does not cause QT prolongation, do not use in pregancy
Ibrexafungerp Drug Interactions
metabolized by and a weak CYP3A4 inhibitor
