Treatment of Fungal PN

Question 1

Candida Albicans (yeast)

Presentation

Answer 1

Fever, tachycardia, patchy infiltrates on CXR

Question 2

Candida Albicans (yeast)

Characteristics

Answer 2

uncommon cause of PN; hematogenous spread seen in immunocompromised patients

Question 3

Candida Albicans (yeast)

Treatment

Answer 3

Amphotericin B (IV) and fluconazole

Question 4

Cryptococcus Neoformans (yeast)

Presentation

Answer 4

Often asymptomatic; may have productive cough, fever and weight loss

Question 5

Cryptococcus Neoformans (yeast)

Characteristics

Answer 5

Associated with pigeon droppings; can produce cryptococcal meningitis

Question 6

Cryptococcus Neoformans (yeast)

Treatment

Answer 6

CNS: Amphotericin B (IV) + Flucytosine (PO)

Non-CNS: Fluconozole (PO)

Question 7

Aspergillus (mold)

Presentation

Answer 7

Wheezing, dyspnea and cough with allergic bronchopulmonary aspergillosis

Fever, cough, dyspnea, pleuritic chest pain, and hemoptysis seen in invasive forms, usually in immunocompromised patients

Question 8

Aspergillus (mold)

Characteristics

Answer 8

Aspergillomas (fungal balls) can form in pre-existing cavities; the invasive form spreads hematogenously

Question 9

Aspergillus (mold)

Treatment

Answer 9

Amphotericin B (IV) or Itraconazole

Updated Rx

• 1st line: voriconazle (IV) with step down to PO
• 2nd line: amphotericin B (IV) with step down to posaconazole (PO)

Question 10

Blastomyces dermatitidis (dimorphic)

Presentation

Answer 10

Fever, chills, productive cough.

May also present wtih skin or bone lesions, or genitourinary involvement

Question 11

Blastomyces dermatitidis (dimorphic)

Characteristics

Answer 11

Causes pneumonia-like lung disease and may progress to disseminated disease

Question 12

Blastomyces dermatitidis (dimorphic)

Treatment

Answer 12

Amphotericin B (IV) or Itraconazole

Updated Rx:

• 1st line: fluconazole (IV) or amphotericin B (IV) if severe. Step down to voriconazole or itraconazole or fluconazole
• 2nd line: amphotericin (IV). Step down to voriconazole or fluconozole (PO)

Question 13

Histoplasma capsulatum (dimorphic)

Presentation

Answer 13

Often asymptomtic; the young or immunocompromised may have disseminated or chronic disease with fever, fatigue and weight loss

Question 14

Histoplasma capsulatum (dimorphic)

Characteristics

Answer 14

Caseating granuloma formation in tissue; the disseminated form is marked by multi-system involvement with macrophage infiltrates filled with intracellular fungi

Question 15

Histoplasma capsulatum (dimorphic)

Treatment

Answer 15

Severe or immunocompromised: Amphotericin B (IV) followed by Itraconazole (PO)

Mild-moderate: Itraconazole PO

• Updated Rx states to use voriconazole, posaconazole or fluconazole (PO) or the mild-moderate disease.

Question 16

Coccidioides immitis (dimorphic)

Presentation

Answer 16

Fever, cough, headache, chest pain

Disseminated or chronic disease produces systemic symptoms

Question 17

Coccidioides immitis

Characteristics

Answer 17

May have acute, disseminated or chronic course.

Fungal spheres containing endospores are found in granulomas.

Question 18

Coccidioides immitis

Treatment

Answer 18

Severe or immunocompromised: Amphotericin B (IV) followed by Itraconazole or Fluconazole (PO)

Mild-moderate: Itraconazole or Fluconazole (PO)

• Updated Rx states to use voriconazole or posaconazole (PO) for the mild-moderate disease

Question 19

Reminder: what is the one indication of fluctyosine?

Answer 19

Cryptococcal infections

Question 20

What is azole resistance by Aspergillus species associated with?

Answer 20

Associated with mutations in the promoter region of CYP51A, which encodes lanosterol-14-alpha-sterol demethylase activity (the drug target of the azoles)

Question 21

What is the only azole able to penetrate the BBB?

Answer 21

Fluconazole

Note that this drug has the BEST TOLERANCE and WIDEST THERAPEUTIC INDEX

Question 22

What is the trend in terms of itraconazole?

Answer 22

Trend to move away from this drug and towards the newer azole drugs, as oral absorption of itraconazole is low and variable from patient to patient.

Drug levels achieved with the newer azoles (fluconazole, voriconazole, posaconazole) are much more consistent.

Question 23

Azoles undergo what form of metabolism?

Answer 23

Hepatic

Interact with concurrent drugs metabolized via CYP2C9, CYP2C19 and CYP3A4

Question 24

Which of the fungal agents do not undergo hepatic metabolism?

Answer 24

Neither amphotericin B nor flucytosine undergo hepatic metabolism. Fluconazole is also eliminated via renal metabolism.

Drug interactions with amphotericin B are possible with other nephrotoxic agents and with drugs producing hypokalemia.

Caution is advised for flucytosine with other hemotoxic drugs becuase flucytosine can itself produce anemia, and blood dyscrasias, including agranulocytosis.

Question 25

Amphotericin B

Answer 25

_MOA_: binds to **ergosterol** (prominent sterol) in fungal cell membranes and increases membrane permeability by forming pores. * binding to human membrane sterols does occur, probably accounting for the drug's prominent renal damage (azotemia, hypokalemia, reduced GFR, renal failure) _Adverse Effects_: * **Immediate infusion-related reactions** including fever, chills, muscle spasms, vomitting, headache, hypotension (premedicate with antipyretics, antihistamines, meperidine, or corticosteroids) * **Delayed renal toxicity** (sodium loading often used to reduce pre-renal toxicity) * **Anemia** secondary to renal damage (result of drug-induced damage and loss of EPO production by kidney) * Abnormal liver fxn tests

Question 26

What is the comparable drug to Amphotericin B?

Answer 26

Nystatin Toxicity prevents systemic administration. Must have topic application in treatment of candidiasis.

Question 27

Azole MOA

Answer 27

Inhibit ergosterol synthesis by **blocking 14-alpha demethylase**, a CYP enzyme needed to convert lanosterol to ergosterol. **Work through CYP450 inhibtion! ** Can be divided into: * **imidazoles**: 2 nitrogens in azole ring (ketoconazole only) * **triazoles**: 3 nitrogens in azole ring

Question 28

Which azole drugs have poor solubility to penetrate into CSF?

Answer 28

Ketoconazole and Itraconazole These drugs are substrates for P-gp located in the BBB

Question 29

Which azole drugs should not be administered during pregnancy?

Answer 29

Fluconazole and Voriconazole

Question 30

Ketoconazole

Answer 30

* Systemic use now discouraged by FDA because of **hepatic toxicity and CYP drug interactions**. * Serious **cardiac effects** have occured when this drug was taken by patients using the antihistamines astremizole or terfenadine * Only one that causes **adrenal insufficiency**: inhibit synthesis of adrenal steroids, leading to reduction in aldosterone, cortisol, and testosterone (may be employed in treatment of hormone-sensitive prostate cancer)

Question 31

Voriconazole

Answer 31

Good oral bioavailabiliy; clinically relevant inhibitor of mammalian CYP3A4 * drug-drug interactions including cyclosporine and tacrolimus * associated with: photosensitive dermatitis, elevated liver enzymes, temporary visual distrubances upon IV adminstration, neurologic symptoms such as hallucinations

Question 32

What is the only azole with activity against mucormycosis?

Answer 32

Posaconazole Orally administered; CYP mediated drug-drug interactions

Question 33

Some of the azole drugs are associated with what cardiac issues?

Answer 33

Pro-arrythomogenic events (i.e. cardiac arrythmia)

Question 34

Flucytosine (5-FC) MOA and Adverse Effects

Answer 34

_MOA_: **nucleic acid synthesis inhibitor** that prevents cell replication * **pyrimidine analogue** with NARROW therapeutic window * enters fungal cells via enzyme **cytosine permease**; converted to 5-FC; becomes incorporated into intermediary metabolism. Inital conversion NOT possible in mammalian cells BUT is mediated in intestinal microflora Good oral absorption; extensive distribution _Adverse Effects_: * **Renal elimination**; toxicity increased in renal impairement * **Anemia, leukopenia, thrombocytopenia** * **Elevated hepatic enzymes**

Question 35

Terbinafine MOA and Adverse Effects

Answer 35

_MOA_: blocks conversion of **squalene to squalene epoxide**, causing interruption in cell wall synthesis and leads to accumulation of squalene which is toxic _Adverse Effects_ * No effect on CYP activity * Generally well tolerated * **Transient lymphopenia and neutropenia** with oral drug so avoid in immunosuppresed patients and perform routine CBCs

Question 36

Capsofungin (Echinocandins) MOA and Adverse Effects

Answer 36

_MOA_: **inhibitor of beta 1-3 glucan** (structural component of cell membrane) leading to loss of fungal cell membrane structure and integrity _Usage_: IV agaisnt Aspergillus and Candida sp _Adverse Effects_ * Very well tolerated if used alone * Minor GI upset * Infusion reaction: chills, fever, flushing, headache * Rare elevation of hepatic enzyme levels

Question 37

Griseofulvin MOA and Adverse Effects

Answer 37

_MOA_: **inhibition of mitotic spindle** in cell nucleus _Usage_: Limited clinical utility; systemic treatmetn of dermatophytosis (treat severe fungal skin infections, onchomycoses, and tinea). Poor penetration if given topically, largely replaced by terbinafine.

Question 38

What are some notable drug interactions?

Answer 38

* Griseofulvin is a CYP3A4 inducer producing drug-drug interactions with reduced clinical activity of Warfarin, oral contraceptive agents, cyclosporine * Ketoconazole and warfarin

Question 39

What are the classical mechanisms of resistance?

Answer 39

1. Modification of drug target (e.g. Amphotericin B) 2. Down-regulation of activation pathways or upregulation of protective mechanisms (e.g. azoles, flucytosine, capsofungin) 3. Active energy-dependent efflux pumps remove toxic drug concentrations from within the cell