Fungal Pathogens - Aspergillus - A mold that is ubiquitous in the environment - Primarily causes disease in ___ hosts ( ___ ) - Pulmonary system is most common infection (can occur anywhere though) - Definitive diagnosis requires a positive culture from a sterile site - Can also use histologic or radiologic evidence in a high- risk patient with negative cultures - Very difficult infection to treat!

- immunocompromised, neutropenia

Amphotericin - Fast Facts - Poorly absorbed after PO administration - requires ___ , intrathecal, intraventricular, topical, or bladder instillation - Rapidly and widely distributed into tissues - Poor penetration into CSF, even if meninges are inflamed (~3% of serum) - Highly protein bound (> 90%) - Not appreciably ___ ~3% is excreted in the urine as active drug (most of the drug is degraded in situ) Tri-exponential elimination - Half life ~ 24-48 hr - terminal elimination half life ___ days (serum concentrations detected for at least 7 weeks after end of therapy) ___ and ___ impairment and ___ do not affect drug clearance ___ formulations → 80-90% ___ in kidney concertation - Lipid formulations also have different PK patterns

- IV - metabolized - 15 - renal, hepatic, hemodialysis - lipid - reduction

Itraconazole (Sporanox) - Metabolized predominantly by ___ (inhibitor) Active metabolite – ___ Long elimination half-life 30-40 hours Clearance ___ with higher doses due to saturable hepatic metabolism No dosage adjustment for renal dysfunction! Not removed by HD or PD Widely distributed throughout body tissue - Poor CSF penetration Good absorption after oral administration (capsules F » 55%) – dependent on ___ acidity Capsules absorbed better when taken with meal or acidic cola beverage Oral ___ better absorbed in fasting state (F » 80%) – not affected by gastric acidity Oral solution better absorbed than capsules – not interchangeable

- CYP3A4 - hydroxyitraconazole - decreases - gastric - solution

Antifungal Agents Flashcards by Reagan Smith

Fungal Pathogens – Candida

Normal flora of the human gastrointestinal tract (yeast)
Can cause more mild infections such as oropharyngeal or esophageal candidiasis, uncomplicated candiduria, and vulvovaginal candidiasis
Can also cause serious invasive diseases such as catheter-associated infections and disseminated disease (invasive candidiasis refers to severe forms of the disease)
Increased mortality if empiric antifungal therapy is delayed by ___ 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

## 12

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Fungal Pathogens - Aspergillus

A mold that is ubiquitous in the environment
Primarily causes disease in ___ hosts ( ___ )
Pulmonary system is most common infection (can occur anywhere though)
Definitive diagnosis requires a positive culture from a sterile site
Can also use histologic or radiologic evidence in a high- risk patient with negative cultures
Very difficult infection to treat!

immunocompromised, neutropenia

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Fungal Pathogens - Zygomycetes

Rhizopus, Absidia, Mucor, and Rhizomucor
Most common infections: pulmonary system, paranasal sinuses with extension to the brain, and skin infections in patients with thermal burn injury

Primary risk factors:
- Diabetes mellitus
- ___ (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 ___ prognosis, extremely high ___

Immunosuppression
poor, mortality

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Fungal Pathogens – Endemic Fungi

Histoplasma capsulatum, Blastomyces species, Coccidioides species
- 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)

___ – Midwestern states along Ohio and Mississippi river valleys; exposure to bat guano (cave exploration) or other large birds; demolition or construction

___ – 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)

Histoplasma capsulatum
Blastomyces species

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Fungal Pathogens – Cryptococcus

Two common species - ___ and cryptococcus gattii
- Encapsulated yeast that primarily affects the ___ and respiratory tract
- More common in patients who are infected with HIV, who have received organ transplants, or high-dose corticosteroids

Cryptococcal ___
- 30% mortality
- Residual neurologic deficits in 40%

Cryptococcus neoformans
CNS
meningitis

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Amphotericin B

Formulations and MOA
- Binds to ___ and gets inserted into the fungal cytoplasmic membrane → Disruption of the fungal cytoplasmic ___
- Increased cell ___ → ___ of sodium/potassium/cellular constituents, loss of membrane potential, metabolic disruption
- cell death

ergosterol, membrane
permeability, Leakage

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Amphotericin

Spectrum of Activity
1st line for (4)

Commonly used as initial agent in ___ invasive fungal infections such as Histoplasmosis / Blastomyces and Cryptococcal meningitis

Cryptococcus
Blastomyces
Histoplasma
Mucor
systemic

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Amphotericin - Fast Facts

Poorly absorbed after PO administration - requires ___ , intrathecal, intraventricular, topical, or bladder instillation
Rapidly and widely distributed into tissues
Poor penetration into CSF, even if meninges are inflamed (~3% of serum)
Highly protein bound (> 90%)
Not appreciably ___ ~3% is excreted in the urine as active drug (most of the drug is degraded in situ)

Tri-exponential elimination
- Half life ~ 24-48 hr
- terminal elimination half life ___ days (serum concentrations detected for at least 7 weeks after end of therapy)

___ and ___ impairment and ___ do not affect drug clearance

___ formulations → 80-90% ___ in kidney concertation
- Lipid formulations also have different PK patterns

IV
metabolized
15
renal, hepatic, hemodialysis
lipid
reduction

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Amphotericin - dosing

Deoxycholate
- total daily dose to 0.3-1.0 mg/kg/day
- usual ___ - ___ mg/kg/day
- up to 1.5mg/kg for difficult to treat infections (aspergillosis and muco)
- Traditionally infused over 4-6 hours -> data suggest significantly fewer adverse events if administered as continuous infusion over 24 hr

Liposomal
- 1.5-6 mg/kg/day
- Most commonly ___ - ___ mg/kg daily
- Infused over 2 hours

Lipid Complex
- ___ mg/kg daily
- Infused at 2.5mg/kg/hour

DOSE BASED ON ___ BODY WEIGHT OR ___ BODY WEIGHT

0.5-1 mg/kg/day
3-5 mg/kg daily
5 mg/kg daily
ideal, adjusted

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Amphotericin - Adverse Effects

Infusion related reactions
- Headache, fever, chills, arthralgias, myalgias, N/V, tachypnea, hypotension
- Pretreat with acetaminophen, antihistamines

___ !!! – Dose dependent
- Cause increase in ___ and ___
- Can be permanent
- Prevention: 0.5-1 L normal saline over 30 minutes before AMB and 0.5-1 L
normal saline after completion of infusion. Hydration!
- Can adjust dose if this occurs not for renal dysfunction just to lessen side
effect

Electrolyte abnormalities
- Hypo ___ and ___
- Bicarbonate wasting

Anemia

Nephrotoxicity, SCr, BUN
Hypokalemia, Hypomagnesemia

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Amphotericin - Drug Interactions

Nephrotoxic agents: risk of nephrotoxicity
Digoxin and Skeletal muscle relaxants: risk of ___
___ : increases therapeutic effect
(which increases toxicity risk)

hypokalemia
Flucytosine

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Flucytosine MOA

Flucytosine (5-FC) enters fungal cell
- Deaminated to ___by cytosine deaminase
- 5-FU gets incorporated into fungal ___
- Interference with protein synthesis

also metabolised to 5-Fdump
- inhibits ___ synthetase
- Interferes with ___ synthesis

5-FU
RNA
thymidylate
DNA

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Flucytosine - Fast Facts

Great ___ (>90%)
- Penetrates into the ___ (~75% of serum)
- Main use is combo therapy with AmphoB for Cryptococcal ___

Can do TDM to adjust dose

85-95% excreted unchanged in the urine
* Removed by HD and PD
* Half life 3-5hrs
* ___ dose adjusted

bioavailability
CSF
meningitis
Renally

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Flucytosine

Spectrum of Activity
1st line for ___

Cryptococcus

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Flucytosine Dosing

___ mg/kg/DOSE po Q6H
- In those with renal dysfunction we don’t change mg/kg dose just frequency of the dose

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Flucytosine Adverse Effects

Gastrointestinal
- N/V/D
- Abdominal pain
- Enterocolitis

Hematologic
- ___ suppression (associated with high peak concentrations)

Monitor: ___ , ___ , ___ , and ___
* No significant drug interactions

bone marrow
CBC, platelets, Scr, BUN

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Azole Antifungal Agents

Class MOA: Inhibits synthesis of ergosterol via inhibition of the fungal cytochrome P-450 dependent enzyme lanosterol ___

14-α-demethylase

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T or F: Ketoconazole should never be used orally for first-line therapy of any fungal infection due to risk of hepatotoxicity and drug interactions

TRUE

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Fluconazole (Diflucan)

___ >90%
- Independent of gastric pH (no food restrictions)

Decent ___ concentration
* 60% of serum in uninflamed meninges
* 80% in inflamed

Excreted ___ in the urine
- Dose reduce in ___ insufficiency
- Removed by HD (50% in 3 hour run)

Half life ~30 hours (daily dosing)

Dosing based on ___ body weight

Potent inhibitor of CYP2C9, moderate inhibitor of CYP3A4

Bioavailability
CSF
unchanged, renal
total

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Fluconazole Clinical Use

Noninvasive candidiasis
* Oropharyngeal – 200 mg on day 1, then 100-200 mg daily for 2 weeks
* Esophageal – 400 mg on day 1, then 200-400 mg daily for 14-21 days
* Vaginal – 150 mg x 1 dose

1st Line: Invasive candidiasis (aka Candidemia)
* if ___ : 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily
* if ___ : 800 mg daily (loading dose 1200- 1600 mg) – dependent on susceptibility

Prophylaxis in BMT:400mg daily

Cryptococcal meningitis
* Inferior alternative to amphotericin B ± flucytosine for ___ therapy
* ___ therapy 800 mg daily for 10-12 weeks after CSF negative
* ___ therapy – 400 mg daily for at least 1 year AND remains asymptomatic from
cryptococcal infection AND CD4 count ³ 100 cells/μL for ³ 3 months and suppressed HIV RNA in response to effective antiretroviral therapy (if infected with HIV

C. albicans
C. glabrata
induction
Consolidation
Maintenance

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Fluconazole Adverse Effects

Headache
Nausea
Anorexia
___
Elevation of hepatic transaminases
Adrenal insufficiency

QTc prolongation

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Fluconazole - Spectrum of Activity

1st line (5)

candida albicans
candida parapsilosis
candida tropicalis
candida lusitaniae
coccidioides

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Itraconazole (Sporanox)

Metabolized predominantly by ___ (inhibitor)
Active metabolite – ___
Long elimination half-life 30-40 hours
Clearance ___ with higher doses due to saturable hepatic metabolism
No dosage adjustment for renal dysfunction! Not removed by HD or PD
Widely distributed throughout body tissue - Poor CSF penetration
Good absorption after oral administration (capsules F » 55%) – dependent on ___ acidity
Capsules absorbed better when taken with meal or acidic cola beverage
Oral ___ better absorbed in fasting state (F » 80%) – not affected by gastric acidity
Oral solution better absorbed than capsules – not interchangeable

CYP3A4
hydroxyitraconazole
decreases
gastric
solution

SUBA - Itraconazole (Tolsura)

Uses a “solid dispersion” in a polymer to increase the absorbency of drugs in the gastrointestinal tract to enhance the bioavailability
Comparable steady-state Cmax, Ctrough, and AUC for SUBA-itra 130 mg (2x65 mg caps) as itraconazole 200 mg (2x100 mg caps)
Absorption NOT affected by ___ acidity
May be given with or without food (recommended to give with ___ )

gastric
food

# Itraconazole Fast Facts - 1st line Histoplasmosis: **200 mg PO ___ x 3 days, then 200 mg PO ___** Blastomycosis: 200 mg PO TID x 3 days, then 200 mg PO BID

- TID, BID

# Itraconazole Adverse Effects - ___ toxicity - ___ (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 - ___ - Pseudohyperaldosteronism (new or worsening hypertension and hypokalemia) - Peripheral neuropathy - GI – nausea, abdominal discomfort - Rash - Contraindicated in pregnancy and nursing mothers - Serum trough itraconazole concentrations > __ - __ μg/ml * troughs > ___ μg/ml combined itraconazole and hydroxyitraconazole associated with efficacy * Serum trough concentrations > 3 μg/ml associated with increased adverse events

- hepatotoxicity - CHF - QTc prolongation - 0.5-1 - 1.5

# Itraconazole Drug Interactions H2 antagonists, proton pump inhibitors, antacid – ___ absorption of itraconazole capsules Drugs metabolized by CYP 3A4 – potent ___ * 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

- decrease - inhibitor

# Itraconazole Spectrum of Activity 1st line: ___ and ___

- Blastomyces, Histoplasma

# Posaconazole (Noxafil) Oral suspension - Absorption affected by ___ pH - decreased absorption with PPIs - Not reliable bioavailability Delayed release tablets - absolute bioavailability 54% - not interchangeable with oral suspension - ___ oral formulation - absorption not affection by gastric pH Suspension and tablets better absorbed when administered with food Suspension better absorbed when administered in divided doses 14% of administered dose recovered in urine / 71% in feces Half-life ~26-35 hours IV formulation contains ___ – AVOID if CRCL < ___ ml/min

- gastric - preferred - cyclodextrin, 50

# Posaconazole AE - N/V/D - Abdominal pain - ___ - __ AST/ALT/Bilirubin - Hypokalemia - Rash - Pseudohyper- aldosteronism

- QTc prolongation - ↑

# Posaconazole - Spectrum of Activity

not first line for anything

# Voriconazole (Vfend) Distribution: extensive tissue distribution Metabolism - Significantly metabolized by CYP ( ___ , ___ , and ___ ) * Metabolism is saturable – pharmacokinetics are non-linear Elimination * < 2% of dose excreted unchanged in urine * Half-life 6 hours (dose-dependent) * NO dosage adjustment necessary for ___ dosing * In patients with ClCr 30-50 ml/min, accumulation of the intravenous vehicle * AVOID IV VORICONAZOLE IF CLCR < ___ ML/MIN (due to vehicle) Absorption - Oral bioavailability ~96% (**NOT affected by H2 antagonists, PPI, antacids**) * Tablets and oral suspension should be taken 1 hour before or after meals (administration with food decreases exposure by 22%)

- 2C19, 2C9, 3A4 - oral - 50

# Voriconazole Clinical Use 1st line: Invasive ___ * Oral maintenance dose should be decreased by 50% in mild-to-moderate ___ cirrhosis * Dosing should be based on ideal body weight or adjusted body weight (TDM)

- aspergillosis - hepatic

# Voriconazole Adverse Effects - ___ disturbances (20-30%) – blurred vision, color changes, photophobia, photopsia, hallucinations * Elevated ___ function tests (13%; up to 33% with high dose) – aminotransferases, alkaline phosphatase, bilirubin * CNS – cognitive difficulties, memory loss with high dose * Peripheral neuropathy (9%) * QTc ___ * ___ 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 ___ secondary to excess fluoride (voriconazole contains fluorine) - associated with prolonged therapy; non-specific pain in hands, finger swelling, diffuse musculoskeletal pain

- Visual - liver - prolongation - Phototoxic - periostitis

# Isavuconazole Adverse Effects T or F: Does not cause QT prolongation (can actually shorten)

TRUE

# Isavuconazole Drug Interactions Drug Interactions – Overall considered to be the ___ DI in the azole family - no dosage adjustment for renal impairment or ESRD - usually ___ line therapy

least last

# Azole AE Review - ___ dysfunction - QTc prolongation (one exception) - GI intolerance - Many drug interactions!

- Hepatic - isavuconazole

# Echinocandins MOA - Glucan synthesis inhibitor leading to noncompetitive inhibition ___ , an integral polysaccharide component of fungal cell wall -> fungicidal

- 1,3-β-D-glucan

# Echinocandins SOA 1st line: 4 | may add micafungin to voriconazole in severe Aspergillus infections

- C. glabrata - C. krusei - C. lusitaniae - C. auris

# Caspofungin Adverse Effects - ___ - mediated symptoms – rash, facial swelling, pruritus, flushing - Fever - ___ at infusion site - N/V - headache

- Histamine - Phlebitis

# Micafungin (Mycamine) - not absorped orally - give ___ - No dosage adjustment for ___ dysfunction - Drug Interactions - not metabolized via CYP

- IV - renal

# Micafungin Clinical Use Candidemia -___ mg ___

- 100 mg daily

# Micafungin Adverse Effects 1) __ 2) N/D 3) __ 4) Rash, pruritus, urticarial (rare)

1) Hyperbilirubinemia 2) Eosinophilia

# Ibrexafungerp Clinical Use - ___ candidiasis (VVC) - Recurrent VVC - Verify ___ status prior to initiating treatment – contraindicated - Use effective contraception during and for ___ days after treatment

- Vulvovaginal - pregnancy - 4

# Candida SOA ___ and ___ class cover the fungi

fluconazole, Echino

# Spectrum of Activity (Misc) fluconazole (2) Itraconazole (2) Vori (1) Ampho (2) Flucytosine (1)

fluconazole 1) Cryptococcus 2) Coccidioides Itraconazole 1) Blastomyces 2) Histoplasma Vori 1) Aspergillus Ampho 1) Cryptococcus 2) Mucor Flucytosine 1) Cryptococcus

# Oropharyngeal & Esophageal Candidiasis Primary line of host defenses against superficial Candida infections is ___ immunity (mediated by CD 4 T-cells)

- cell-mediated

# Esophageal Candidiasis Clinical Presentation - Dysphagia, odynophagia, and retrosternal ___ pain are common - ___, few to numerous white or beige plaques of varying size * Plaques can be hyperemic or edematous with ulceration in severe cases * Upper GI endoscopy with biopsy * Histologic presence of Candida in lesions * Culture warranted; concern for drug ___

- chest - Fever - resistance

# Treatment Oropharyngeal Candidiasis Treat for ___ - ___ days Topical therapy for mild infection - ___ 10 mg troche (hold in mouth for 15-20 minutes for slow dissolution) 5x/day - ___ 100,000 units/ml suspension, 5 mL swish and swallow, QID - Miconazole 50 mg mucoadhesive buccal tablet, apply to upper gum region daily x 7-14 days

- 7-14 - Clotrimazole - Nystatin

# Treatment Oropharyngeal Candidiasis Treatment Fluconazole Refractory OPC - Treat for ≥ 14 days (up to 28 days) - ___ solution 200 mg daily

- Itraconazole

# Treatment Esophageal Candidiasis - Treat for ___ - ___ days - ___ therapy always required Fluconazole ___ -400 mg PO/IV daily

- 14-21 - systemic - 200

# Vulvovaginal Candidiasis Uncomplicated – sporadic infection that is susceptible to all forms of antifungal therapy regardless of treatment duration Complicated – recurrent VVC; severe disease; non- ___ infection; host factors (DM, immunosuppression, ___ )

- Candida albicans - pregnancy

# Vulvovaginal Candidiasis Increased incidence when women become sexually active Contraceptive agents increase risk of VVC - Oral contraceptives ( ___ dose pills) - Diaphragm with spermicide, contraceptive sponge, IUD ___ use! Increased incidence in post-menopausal women taking HRT - No established association with diet (excess refined carbs), douching, or tight-fitting clothing

- high - antibiotic

# Vulvovaginal Candidiasis Uncomplicated VVC - Cure rates 80-95% with topical or oral azoles (therapeutically ___ ) - Cure rates 70-90% with ___ Topical preparations can decrease efficacy of ___ condoms and diaphragms

- equivalent - nystatin - latex

# Vulvovaginal Candidiasis Treatment OTC/topical vaginal products

- Butoconazole - Clotrimazole - Miconazole - Tioconazole

# Vulvovaginal Candidiasis Treatment Prescription topical - ___ - ___ Prescription oral - ___ 150 mg tablet, 1 tablet PO x 1 day - Ibrexafungerp 300 mg PO twice daily x 1 day

- nystatin - terconazole - fluconazole

# Treatment of Complicated VVC Same drugs as treatment of uncomplicated VVC but extend duration of therapy to ___ - ___ days, regardless of route of administration - Fluconazole 150 mg x 2-3 doses, 72 hours apart

- 10-14