antifungal agents

Question 1

Candida species

Answer 1

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

Question 2

aspergillus

Answer 2

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

Question 3

Cryptococcus neoformans

Answer 3

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%

Question 4

Zygomycetes

Answer 4

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

Question 5

endemic (pathogenic) fungi

Answer 5

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)

Question 6

amphotericin B MOA

Answer 6

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

Question 7

amphotericin B SOA

Answer 7

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

Question 8

amphotericin B doexycholate PKs

Answer 8

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

Question 9

Amphotericin B lipid-associated formulations PKs

Answer 9

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

Question 10

amphotericin B clinical uses

Answer 10

Disseminated candidiasis
Cryptococcosis
Aspergillosis
Histoplasmosis
Blastomycosis
Coccidioidomycosis
Mucormycosis

Question 11

amphotericin B doexycholate dosing and administration

Answer 11

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

Question 12

L-AmB dosing and admin

Answer 12

1.5-6 mg/kg daily, infused over 2 hours (if using an in-line filter, mean pore diameter must be ≥ 1 micron)

Question 13

ABLC dosing and admin

Answer 13

5 mg/kg daily, infused at 2.5 mg/kg/hr

Question 14

ABCD dosing and admin

Answer 14

3-4 mg/kg daily, infused at 1 mg/kg/hour (administer test dose; infusion may be shortened to 2 hours if no reactions)

Question 15

ampB deoxycholate adverse reactions

Answer 15

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

Question 16

ampB lipid-associated formulation adverse reactions

Answer 16

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

Question 17

ampB DIs

Answer 17

Nephrotoxic agents – potentiation of nephrotoxicity
Digoxin and skeletal muscle relaxants – potentiation secondary to hypokalemia
Flucytosine – increase therapeutic effect; potential for increased toxicity

Question 18

flucytosine MOAs

Answer 18

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

Question 19

flucytosine SOA

Answer 19

Cryptococcus neoformans**

Candida species

Question 20

flucytosine PKs

Answer 20

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

Question 21

flucytosine clinical use

Answer 21

Combination therapy with amphotericin B for cryptococcal meningitis

Question 22

flucytosine adverse reactions

Answer 22

Gastrointestinal (6%) – nausea, vomiting, diarrhea, abdominal pain, enterocolitis
Hematologic – Bone marrow suppression (more common with serum concentrations > 100 µg/ml)

Question 23

flucytosine dosing/monitoring

Answer 23

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

Question 24

ketoconazole MOA

Answer 24

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)

Question 25

ketoconazole SOA

Answer 25

Candida albicans Cryptococcus neoformans Histoplasma capsulatum Dermatophytes (tinea)

Question 26

ketoconazole PKs

Answer 26

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

Question 27

ketoconazole clinical uses

Answer 27

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

Question 28

ketoconazole adverse reactions

Answer 28

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

Question 29

ketoconazole DIs

Answer 29

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

Question 30

Itraconazole MOA

Answer 30

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)

Question 31

itraconazole SOA

Answer 31

``` Aspergillus spp.** Histoplasma capsulatum Blastomyces dermatitidis Candida species Coccidioides immitis Cryptococcus neoformans Sporothrix schenckii ```

Question 32

itraconazole PKs

Answer 32

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

Question 33

Itraconazole clinical uses/indications

Answer 33

Histoplasmosis (first choice) – 200 mg PO daily (max dose 400 mg/day in 2 divided doses) Aspergillosis (not first-line) – 200 to 400 mg PO daily Blastomycosis – 200 mg PO daily (max dose 400 mg/day in 2 divided doses) Life-threatening infections – administer oral loading dose of 200 mg three times daily for first 3 days of therapy, then 200-400 mg PO daily Onychomycosis of toenails – 200 mg PO daily for 12 consecutive weeks 6. Onychomycosis of fingernails – 200 mg PO BID for 1 week; repeat 3 weeks later

Question 34

itraconazole therapeutic drug monitoring

Answer 34

Serum trough concentrations of 0.5-1 µg/ml associated with efficacy Serum trough concentrations > 3 µg/ml associated with increased adverse events

Question 35

itraconazole adverse reactions

Answer 35

Hepatotoxicity Congestive heart failure (boxed warning)*** – contraindicated in patients with ventricular dysfunction (CHF) or history of CHF → may cause negative inotropic effect; discontinue if signs/symptoms of CHF occur on therapy Peripheral neuropathy GI – nausea, abdominal discomfort Rash Contraindicated in pregnancy and nursing mothers

Question 36

itraconazole DIs

Answer 36

H2 antagonists, proton pump inhibitors, antacid – decrease itraconazole absorption Drugs metabolized by CYP 3A4 – potent inhibitor -Increased drug concentrations if administered with itraconazole: digoxin, quinidine, benzodiazepines, HMG-CoA reductase inhibitors (not pravastatin), rifabutin, cyclosporine, tacrolimus, sirolimus, protease inhibitors (ritonavir, indinavir, saquinavir) -Decreased plasma concentrations of itraconazole: carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, nevirapine -Increased concentrations of itraconazole: clarithromycin, indinavir, ritonavir

Question 37

fluconazole MOA

Answer 37

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)

Question 38

fluconazole SOA

Answer 38

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

Question 39

fluconazole PKs

Answer 39

Absorption -Well absorbed orally (Tmax 1-2 hr); independent of gastric acidity; may be administered without regards to food -Bioavailability > 90% & linear Distribution -Protein binding 11% -Concentration in the CSF – 60 % of serum with uninflamed meninges; 80% of serum with inflamed meninges Metabolism/Elimination -Excreted unchanged in urine – 80% recovered unchanged in urine -Elimination half-life ≈ 30 hours -Dosage reduction required in renal insufficiency -3 hour hemodialysis decreases serum concentrations by 50%

Question 40

fluconazole clinical uses/dosing

Answer 40

Noninvasive candidiasis -Oropharyngeal – 200 mg on day 1, then 100 mg daily for 2 weeks -Esophageal – 200 mg on day 1, then 100 mg daily for minimum of 3 weeks (max 400 mg if poor response) -Vaginal – 150 mg x 1 dose Invasive candidiasis (e.g., candidemia) – 800 mg loading dose, then 400 mg daily Prophylaxis in patients undergoing bone marrow transplantation – 400 mg daily Candida urinary tract infection – 100-200 mg daily Cryptococcal meningitis -Alternative to amphotericin B ± flucytosine – 400 mg daily for 10-12 weeks after CSF negative -Maintenance therapy – 200 mg daily (may be discontinued if CD4 count > 200 cells/mm3 for 6 months if no signs/symptoms of meningitis)

Question 41

fluconazole adverse reactions

Answer 41

Headache, nausea, anorexia QT prolongation, torsades de pointes Elevation of hepatic transaminases – may be seen with higher doses

Question 42

fluconazole drug interactions

Answer 42

Potent inhibitory of CYP2C9 | Moderate inhibitor of CYP3A4

Question 43

voriconazole MOA

Answer 43

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)

Question 44

voriconazole SOA

Answer 44

``` 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 ```

Question 45

voriconazole PKs

Answer 45

Absorption -Oral bioavailability ≈ 96% (not affected by H2 antagonists, PPI, antacids) -Tablets and oral suspension should be taken 1 hour before or after meals Distribution -Extensive tissue distribution (Vd 4.6 L/kg) -Protein binding ≈ 58% Metabolism -Significantly metabolized by cytochrome P450 isoenzymes (2C19, 2C9, 3A4)*** -2C19 – genetic polymorphism (15-20% of Asian population, 3-5% of African American and white populations expected to be poor metabolizers) -Poor metabolizers – 4-fold higher AUC Metabolism is saturable – pharmacokinetics are non-linear*** (2.5-fold increase in AUC with 300 mg PO q12h compared to 200 mg PO q12h; 2.3-fold increase in AUC with 4 mg/kg IV q12h compared to 3 mg/kg IV q12h) Elimination -less than 2% of dose excreted unchanged in urine -Half-life 6 hours (dose-dependent) -No difference in Cmax and AUC in mild to severe renal dysfunction ---NO dosage adjustment necessary for ORAL* dosing ---In patients with Clcr 30-50 ml/min, accumulation of the intravenous vehicle, sulfobutyl ether beta-cyclodextrin sodium (SBECD) ---AVOID IV VORICONAZOLE IF CLCR under 50 ML/MIN****

Question 46

voriconazole clinical uses/dosing

Answer 46

Oral and IV maintenance doses do not produce the same voriconazole exposures. A 200 mg oral dose provides an exposure similar to a 3 mg/kg IV dose; 300 mg oral dose provides an exposure similar to a 4 mg/kg IV dose. If inadequate response, increase oral maintenance dose to 300 mg q12h Adults who weigh less than 40 kg should receive half of the oral maintenance dose. Oral maintenance dose should be decreased by 50% in mild-to-moderate hepatic cirrhosis

Question 47

Voriconazole AEs

Answer 47

``` Visual disturbances** (20-30%) – blurred vision, color changes, photophobia, photopsia, hallucinations Elevated liver function tests (13%; up to 33% with high dose) – aminotransferases, alkaline phosphatase, bilirubin CNS – cognitive difficulties, memory loss with high dose Peripheral neuropathy (9%) Phototoxic skin reactions – may progress to squamous cell carcinoma (risk factors: prolonged treatment [> 6 months], strong sun exposure, ongoing immunosuppression or post-transplant phase, advanced age, light-colored skin) Diffuse, painful periostitis secondary to excess fluoride (voriconazole contains fluorine) – associated with prolonged therapy; non-specific pain in hands, finger swelling, diffuse musculoskeletal pain ```

Question 48

Voriconazole therapeutic drug monitoring

Answer 48

Trough concentrations > 1 µg/ml associated with clinical response Trough concentrations > 5.5 µg/ml associated with higher incidence of CNS adverse events

Question 49

Voriconazole drug interactions

Answer 49

Effect of other drugs on voriconazole – sig. decrease in voriconazole exposure -Rifampin, rifabutin, carbamazepine (potent CYP 450 inducer) – co-administration contraindicated Effect of voriconazole on other drugs – increased exposure due to inhibition of metabolism -Sirolimus, terfenadine, astemizole, cisapride, pimozide, quinidine – contraindicated -Cyclosporine, tacrolimus, warfarin, statins, benzodiazepines, calcium channel blockers, sulfonylureas, vinca alkaloids – careful monitoring and dosage adjustment required -Protease inhibitors – ritonavir, saquiavir, amprenavir (no effect with indinavir)

Question 50

Posaconazole MOA

Answer 50

blocks synthesis of ergosterol – same as other triazole agents

Question 51

Posaconazole SOA

Answer 51

``` Candida species (less active against C. glabrata) Aspergillus species** Cryptococcus neoformans Histoplasma capsulatum Mucor species Coccidioides species ```

Question 52

Posaconazole PKs

Answer 52

Absorption is affected by gastric pH (decreased absorption with PPIs) Oral suspension: Tmax 3-4 hours Delayed release tablets: Tmax 4-5 hours; absolute bioavailability 54% Better absorbed when administered with food or acidic carbonated beverage and when administered in divided doses (200 mg q6h > 400 mg q12h > 800 mg q24h) Protein binding 98%, primarily to albumin ≈ 17% metabolized by glucuronidation (not CYP450) 14% of administered dose recovered in urine; 71% in feces Half-life 26-35 hours IV formulation contains cyclodextrin – AVOID if CRCL less than 50 ml/min***

Question 53

posaconazole clinical uses

Answer 53

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 May be used as salvage therapy for treatment of aspergillosis or Mucor infections

Question 54

posaconazole therapeutic drug monitoring

Answer 54

Trough concentrations < 0.7 µg/ml associated with higher incidence of breakthrough fungal infections during prophylaxis Trough concentrations > 1 µg/ml associated with treatment response for invasive aspergillosis Currently no trough concentration associated with toxicity

Question 55

posaconazole DIs

Answer 55

strong inhibitor of CYP3A4 Cyclosporine – reduce dose to 3/4 of original dose Tacrolimus – reduce dose to 1/3 of original dose Sirolimus – contraindicated Midazolam – dose reduction should be considered Phenytoin – decreased Cmax and AUC of posaconazole Rifabutin – decreased Cmax and AUC of posaconazole PPIs and H2 antagonists – decreased Cmax and AUC of Posaconazole

Question 56

Posaconazole AEs

Answer 56

Nausea, vomiting, abdominal pain, diarrhea – 10-30% Elevated AST, ALT, bilirubin, hypokalemia Rash

Question 57

Isavuconazole MOA

Answer 57

Isavuconazonium sulfate is the prodrug of isavuconazole – metabolized by esterases in blood 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

Question 58

Isavuconazole SOA

Answer 58

Aspergillus specis*** (A. flavus, A, fumigatus, A. niger) Mucor Rhizopus

Question 59

Isavuconazole PKs

Answer 59

Linear pharmacokinetics up to 600 mg of isavuconazole Well absorbed orally – absolute bioavailability 98%; Tmax 2-4 hours IV and oral capsules are bioequivalent May be administered orally with or without food Very large volume of distribution ≈ 450 L Highly protein bound (99% to albumin) Plasma half-life 130 hours Renal excretion is less than 1% – no dosage adjustment for renal impairment or ESRD IV formulation does not contain cyclodextrin Not removed by hemodialysis No dosage adjustment in mild or moderate hepatic impairment

Question 60

Isavuconazole clinical uses and dosing

Answer 60

Invasive aspergillosis in patients ≥ 18 years of age Invasive mucormycosis in patients ≥ 18 years of age IV formulation must be administered through an in-line filter (pore size 0.2-1.2 microns) over at least 1 hour in 250 mL to reduce risk of infusion-related reactions (insoluble drug particulates may form after reconstitution) Oral capsules should be swallowed whole; do not chew, crush, dissolve, or open the capsules

Question 61

Isavuconazole AEs

Answer 61

Most frequent: nausea (26%), vomiting (25%), diarrhea (22%), headache (17%) Hepatic (16%) – increased LFTs (AST, ALT, alkaline phosphatase, total bilirubin); generally reversible and discontinuation of isavuconazole not usually required; severe hepatic events have been reported; evaluate LFTs at the start and during the course of therapy Infusion-related reactions (hypotension, dyspnea, chills, dizziness, paresthesias, hypoesthesia) – discontinue infusion if occurs Hypokalemia (14%) Hypersensitivity and severe skin reactions (anaphylaxis, Stevens Johnson syndrome)

Question 62

Isavuconazole DIs

Answer 62

Isavuconazole is a substrate for CYP3A4, a moderate inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a mild inhibitor of P-glycoprotein CYP3A4 inhibitors/inducers CYP3A4 substrates – isavuconazole increases concentrations of cyclosporine, tacrolimus, sirolimus, midazolam P-glycoprotein substrates (digoxin)

Question 63

Isavuconazole CIs

Answer 63

Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) → significant increase plasma isavuconazole concentrations Co-administration with strong CYP3A4 inducers (rifampin, carbamazepine, St. John’s wort, long acting barbiturates) → significantly decrease plasma isavuconazole concentrations Patients with familial short QT syndrome – isavuconazole shortens QT interval

Question 64

Echinocandin antifungal agents

Answer 64

caspofungin, micafungin, anidulafungin

Question 65

caspofungin MOA

Answer 65

Glucan synthesis inhibitor leading to noncompetitive inhibition 1,3-β-glucan, an integral polysaccharide component of fungal cell wall** Together with chitin, glucan is responsible for the cell wall’s strength and shape – important in maintaining the osmotic integrity of the fungal cell wall***

Question 66

caspofungin SOA

Answer 66

Aspergillus species Candida species, including azole-resistant strains (C. glabrata resistance up to 12%) Less active vs. C. parapsilosis Limited activity against Histoplasma capsulatum, Cryptococcus neoformans, Fusarium, and Mucor

Question 67

caspofungun PKs

Answer 67

Poor oral bioavailability – administered by IV infusion Plasma concentration decline in polyphasic manner -β-phase – half-life 9 to 11 hours -γ-phase – half-life 40 to 50 hours Highly protein bound to albumin (97%) Slowly metabolized by hydrolysis and N-acetylation ≈ 1.4% excreted unchanged in urine No dosage adjustment for renal insufficiency or mild hepatic impairment Not removed by hemodialysis

Question 68

Caspofungin indications/dosing

Answer 68

Candidemia – 70 mg loading dose on day 1, then 50 mg q24h Esophageal candidiasis – 50 mg q24h Empiric therapy of presumed fungal infections in febrile neutropenia – 70 mg loading dose on day 1, then 50 mg q24h Invasive aspergillosis in patients who are refractory to or intolerant to other therapies - 70 mg loading dose on day 1, then 50 mg q24h (may use 70 mg daily) Reduce daily dose to 35 mg in severe hepatic dysfunction

Question 69

caspofungin DIs

Answer 69

Does not induce or inhibit CYP450 system; poor substrate for CYP450 Tacrolimus – decreases AUC, Cmax, and C12h of tacrolimus Cyclosporine – increase caspofungin AUC by 35% Inducers of drug clearance (efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, carbamazepine) – may reduce caspofungin concentrations, may need to increase daily dose to 70 mg

Question 70

caspofungin adverse reactions

Answer 70

Histamine-mediated symptoms – rash, facial swelling, pruritus, flushing Fever Phlebitis at infusion site Nausea, vomiting, headache Laboratory – increased liver transaminases, decreased potassium, eosinophilia, increase in urine protein and RBC’s, decreased hemoglobin/hematocrit

Question 71

Micafungin MOA

Answer 71

inhibits synthesis of 1,3-β-glucan

Question 72

Micafungin SOA

Answer 72

Candida species, including azole-resistant strains (C. glabrata resistance up to 12%) Less active vs. C. parapsilosis Aspergillus species Limited activity against Histoplasma capsulatum, Cryptococcus neoformans, Fusarium, and Mucor***

Question 73

Micafungin PKs

Answer 73

Not absorbed orally – give IV Protein binding 99% Half-life 14-17 hours Metabolized by the liver – no dosage adjustment for renal dysfunction Less than 15% eliminated renally as unchanged drug

Question 74

Micafungin clinical uses/dosing

Answer 74

Oropharyngeal and esophageal candidiasis – 50 to 100 mg daily Candidemia – 100 mg daily Aspergillosis – 150 mg daily Prophylaxis of Candida infections in hematopoietic stem cell transplantation (HSCT) – 50 mg daily

Question 75

micafungin DIs

Answer 75

not metabolized via CYP450 pathways

Question 76

micafungin AEs

Answer 76

``` Hyperbilirubinemia Nausea Diarrhea Eosinophilia Rash, pruritus, urticarial – rare ```

Question 77

anidulafungin MOA

Answer 77

inhibits synthesis of 1,3-β-glucan

Question 78

anidulafungin SOA

Answer 78

Candida species, including azole-resistant strains (C. glabrata resistance up to 12%) Less active vs. C. parapsilosis Aspergillus species Limited activity against Histoplasma capsulatum, Cryptococcus neoformans, Fusarium, and Mucor****

Question 79

anidulafungin PKs

Answer 79

Not absorbed orally – must be administered IV Protein binding – 84% Long half-life: 26.5 hours in patients with fungal infections Not metabolized or renally eliminated → undergoes slow chemical degradation No dosage adjustments required for renal or hepatic dysfunction

Question 80

anidulafungin clinical uses/dosing

Answer 80

Candidemia and other Candida infections (peritonitis, intra-abdominal abscess) – 200 mg loading dose on day 1, then 100 mg daily for 14 days after last positive culture Esophageal candidiasis – 200 mg loading dose on day 1, then 100 mg daily for at least 14 days (at least 7 days after resolution of symptoms) - Significantly higher relapse rate than fluconazole

Question 81

anidulafungin DIs

Answer 81

not a substrate, inducers, or inhibitor of CYP450

Question 82

anidulafungin AEs

Answer 82

``` overall, well-tolerated Histamine-mediated symptoms – rash, urticaria, flushing, pruritus, hypotension Diarrhea Increased LFTs Hypokalemia ```