antifungal agents Flashcards
Candida species
C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. guilliermondii, C. lusitaniae, C. auris* (multidrug-resistant)
Invasive candidiasis refers to severe forms of the disease (not uncomplicated candiduria and oropharyngeal or esophageal candidiasis)
Wide spectrum of invasive disease from catheter-associated infections to disseminated disease
Increased mortality if empiric antifungal therapy is delayed by 12 hours
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
A mold that is ubiquitous in the environment
Primarily causes disease in immunocompromised hosts
Pulmonary system is most commonly affected (can occur anywhere though)
Definitive diagnosis requires a positive culture from a sterile site or histologic or radiologic evidence in a high-risk patient with negative cultures
Very difficult infection to treat
Cryptococcus neoformans
Encapsulated yeast that primarily affects the CNS and respiratory tract
More common in patients who are HIV-positive, who have received organ transplants, or high-dose corticosteroids
Cryptococcal meningitis – 30% mortality; residual neurologic deficits in 40%
Zygomycetes
Pathogens – Rhizopus, Absidia, Mucor
Most common infections: pulmonary system; paranasal sinuses with extension to the brain
Primary risk factors: diabetes mellitus; immunosuppression (with profound neutropenia); penetrating injuries from natural disasters (tornadoes, hurricanes, volcanic eruptions) or combat
Definitive diagnosis: tissue invasion on histopathologic exam with or without microbiologic evidence
Very poor prognosis
endemic (pathogenic) fungi
Pathogens – Histoplasma capsulatum, Blastomyces species, Coccidioides immitis
May cause disseminated disease via a primary pulmonary infection
May cause disease in normal host; higher risk in patients with suppressed cell-mediated immunity (HIV/AIDS, high-dose corticosteroids, TNF-α inhibitor therapy, transplant)
Geographic prevalence
-Histoplasma capsulatum – Midwestern states along Ohio and Mississippi river valleys; exposure to bat guano (cave exploration) or other large birds; demolition or construction
-Blastomyces species – Southeastern and Midwestern states along Ohio and Mississippi river valleys and Great Lakes region
-Coccidioides immitis/posadasii – cluster in southwestern United States (southern Arizona, southern California, southwest New Mexico, west Texas)
amphotericin B MOA
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
2. At low concentrations, K+ channel activity is increased
4
3. At higher concentrations, pores are formed in the membrane
4. Rapid onset of action
5. Resistance – decreased ergosterol biosynthesis, synthesis of alternative sterols
6. Pharmacodynamic parameter – Peak/MIC
amphotericin B SOA
Broad Spectrum Candida species (not C. lusitaniae or C. auris) Cryptococcus neoformans Blastomyces dermatitidis Histoplasma capsulatum Coccidioides immitis Aspergillus species** (reduced activity against A. terreus) Mucor species
amphotericin B doexycholate PKs
Poorly absorbed after PO and IM administration – requires IV, intrathecal, intraventricular, topical, or bladder instillation
Rapidly and widely distributed into tissues – primarily deposits into reticuloendothelial tissues: liver, spleen, bone marrow
Poor penetration into CSF, even if meninges are inflamed (≈3% of serum)
Highly protein bound (> 90%) – mainly to β-lipoproteins
Not appreciably metabolized – ≈ 3% is excreted in the urine as active drug (most of the drug is degraded in situ)
Tri-exponential elimination – t½β 24-48 h; terminal elimination t½ 15 days (serum concentrations detected for at least 7 weeks after end of therapy)
Renal and hepatic impairment and hemodialysis do not affect drug clearance
Amphotericin B lipid-associated formulations PKs
All 3 formulations have different PK patterns
Achieve tissue concentrations from 90% lower to 500% higher than deoxycholate formulation
80-90% reduction in concentrations in the kidneys
amphotericin B clinical uses
Disseminated candidiasis Cryptococcosis Aspergillosis Histoplasmosis Blastomycosis Coccidioidomycosis Mucormycosis
amphotericin B doexycholate dosing and administration
Test dose of 0.1 mg/kg or 1 mg over 20 to 30 minutes (do not pre-medicate)
Increase total daily dose to 0.3-1.0 mg/kg/day (usual 0.4-0.6 mg/kg/day; up to 1.5 mg/kg for aspergillosis and mucor)
Generally infused over 4-6 hours
-May be infused over 1 hour in patients who tolerate slower infusions (fever more common early in therapy compared to 4-h infusion)
-Rapid infusions in patients with severely compromised renal function may develop acute hyperkalemia and ventricular fibrillation
-Data suggest significantly fewer adverse events if administered as continuous infusion over 24 hours (conflicts with PD parameter)
Intrathecal or intraventricular administration – 0.1 mg initially; increase gradually to a maximum of 0.5 mg every 48-72 hours
L-AmB dosing and admin
1.5-6 mg/kg daily, infused over 2 hours (if using an in-line filter, mean pore diameter must be ≥ 1 micron)
ABLC dosing and admin
5 mg/kg daily, infused at 2.5 mg/kg/hr
ABCD dosing and admin
3-4 mg/kg daily, infused at 1 mg/kg/hour (administer test dose; infusion may be shortened to 2 hours if no reactions)
ampB deoxycholate adverse reactions
Infusion-related:
-Headache, fever, chills, arthralgias, myalgias, nausea, vomiting, tachypnea, hypotension
—Pretreat with acetaminophen or aspirin, antihistamines, meperidine, phenothiazines
—Hydrocortisone 25-50 mg may be added to the infusion container
—Tolerance develops over time
-Thrombophlebitis
—Slow infusion (4-6 hrs); rotate infusion sites; in-line filters (>0.22 micron)
—Heparin 500-1,000 units may be added to infusion bag
Non-infusion-related:
-Nephrotoxicity – dose-dependent increase in serum creatinine and BUN
—Mechanism – direct vasoconstriction of afferent renal arterioles resulting in cortical ischemia and decrease in GFR
—Permanent loss of renal function related to total dose
—Management and prevention of nephrotoxicity - Sodium repletion – appears to be useful in patients who are sodium depleted; 0.5-1 L normal saline over 30 minutes before AMB and 0.5-1 L normal saline after completion of infusion; Hydration and adjustment of daily dose
-Hypokalemia – supplementation of 100 mEq/day or more may be required
-Hypomagnesemia
-Bicarbonate wasting
-Anemia – normochromic, normocytic (drug-induced decrease in erythropoietin production); reversible
Intrathecal administration – peripheral nerve pain, headache, vomiting, paresthesias, paraplegia, seizures, difficulty voiding, impaired vision
ampB lipid-associated formulation adverse reactions
Less nephrotoxicity & infusion-related toxicities with lipid-associated formulations (except ABCD had similar infusion-related toxicities [fever, chills] compared to deoxycholate)
High-dose liposomal amphotericiln (7.5 mg/kg/d) associated with high nephrotoxicity rates
L-AmB – manage infusion-related reactions with diphenhydramine
Most studies show similar clinical outcomes to deoxycholate
ampB DIs
Nephrotoxic agents – potentiation of nephrotoxicity
Digoxin and skeletal muscle relaxants – potentiation secondary to hypokalemia
Flucytosine – increase therapeutic effect; potential for increased toxicity
flucytosine MOAs
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 SOA
Cryptococcus neoformans**
Candida species
flucytosine PKs
Absorption – well absorbed orally (> 90%) Distribution -Penetrates into CSF ( ≈75% of serum) -Negligible protein binding (2 to 4%) Metabolism/Excretion -Small amount converted to 5-FU -85 to 95% excreted unchanged in urine -Normal half-life – 3 to 5 hours; anephric half-life – 85 hours -Removed by HD & PD
flucytosine clinical use
Combination therapy 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/monitoring
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 Dysfunction - must be adjusted
Monitoring
-Baseline: CBC, platelets, Scr, BUN
-Reduce dose in patients with bone marrow or GI toxicity
-TDM – trough concentrations 20-40 µg/ml recommended to prevent rapid selection of resistance in yeast
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 SOA
Candida albicans
Cryptococcus neoformans
Histoplasma capsulatum
Dermatophytes (tinea)
ketoconazole PKs
Absorption
-Well absorbed orally (F=75%); peak concentration 1 to 2 hours after oral dosing
-Absorption is inversely related to gastric pH***
Distribution
-Widely distributed throughout body (CSF penetration is negligible)
-Protein binding 95 to 99%
Metabolism/Elimination
-Extensively metabolized in the liver
-Major excretory route is enterohepatic – 85 to 90% excreted in bile & feces
-Biphasic elimination – half-life 2 hours (during the first 8-12 hours); 9 hours thereafter
-Dosage adjustment not needed in renal failure; not removed by HD or PD
ketoconazole clinical uses
Should never be used orally for first-line therapy of any fungal infection due to risk of hepatotoxicity and drug interactions
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 & testosterone synthesis → gynecomastia, decreased libido, oligospermia, loss of hair
-Menstrual irregularities
ketoconazole DIs
very potent inhibitor of CYP3A4
Drugs affecting gastric pH – increase pH, decrease bioavailability
Anticoagulants – prolonged PT
Rifampin – decrease ketoconazole concentrations
Cyclosporine, tacrolimus, sirolimus – increased concentrations
Phenytoin – decreased clearance, increased concentrations
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 SOA
Aspergillus spp.** Histoplasma capsulatum Blastomyces dermatitidis Candida species Coccidioides immitis Cryptococcus neoformans Sporothrix schenckii
itraconazole PKs
Absorption
-Good absorption after oral administration (F ≈ 55%) – dependent on gastric acidity
-Capsules absorbed better when taken with meal or acidic cola beverage
-Oral solution better absorbed in fasting state
-Oral solution better absorbed than capsules – not interchangeable
Distribution
-Widely distributed throughout body tissues (poor CSF penetration)
-Highly protein bound (> 99%)
Metabolism/Elimination
-Metabolized predominantly by cytochrome P450 3A4 isoenzyme (inhibitor)
-Active metabolite – hydroxyitraconazole
-Long elimination half-life 20-36 hours
-Clearance decreases with higher doses due to saturable hepatic metabolism
-No dosage adjustment for renal dysfunction; not removed by HD or PD
