Treatment of Fungal PN Flashcards
Candida Albicans (yeast)
Presentation
Fever, tachycardia, patchy infiltrates on CXR
Candida Albicans (yeast)
Characteristics
uncommon cause of PN; hematogenous spread seen in immunocompromised patients
Candida Albicans (yeast)
Treatment
Amphotericin B (IV) and fluconazole
Cryptococcus Neoformans (yeast)
Presentation
Often asymptomatic; may have productive cough, fever and weight loss
Cryptococcus Neoformans (yeast)
Characteristics
Associated with pigeon droppings; can produce cryptococcal meningitis
Cryptococcus Neoformans (yeast)
Treatment
CNS: Amphotericin B (IV) + Flucytosine (PO)
Non-CNS: Fluconozole (PO)
Aspergillus (mold)
Presentation
Wheezing, dyspnea and cough with allergic bronchopulmonary aspergillosis
Fever, cough, dyspnea, pleuritic chest pain, and hemoptysis seen in invasive forms, usually in immunocompromised patients
Aspergillus (mold)
Characteristics
Aspergillomas (fungal balls) can form in pre-existing cavities; the invasive form spreads hematogenously
Aspergillus (mold)
Treatment
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)
Blastomyces dermatitidis (dimorphic)
Presentation
Fever, chills, productive cough.
May also present wtih skin or bone lesions, or genitourinary involvement
Blastomyces dermatitidis (dimorphic)
Characteristics
Causes pneumonia-like lung disease and may progress to disseminated disease
Blastomyces dermatitidis (dimorphic)
Treatment
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)
Histoplasma capsulatum (dimorphic)
Presentation
Often asymptomtic; the young or immunocompromised may have disseminated or chronic disease with fever, fatigue and weight loss
Histoplasma capsulatum (dimorphic)
Characteristics
Caseating granuloma formation in tissue; the disseminated form is marked by multi-system involvement with macrophage infiltrates filled with intracellular fungi
Histoplasma capsulatum (dimorphic)
Treatment
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.
Coccidioides immitis (dimorphic)
Presentation
Fever, cough, headache, chest pain
Disseminated or chronic disease produces systemic symptoms
Coccidioides immitis
Characteristics
May have acute, disseminated or chronic course.
Fungal spheres containing endospores are found in granulomas.
Coccidioides immitis
Treatment
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
Reminder: what is the one indication of fluctyosine?
Cryptococcal infections
What is azole resistance by Aspergillus species associated with?
Associated with mutations in the promoter region of CYP51A, which encodes lanosterol-14-alpha-sterol demethylase activity (the drug target of the azoles)
What is the only azole able to penetrate the BBB?
Fluconazole
Note that this drug has the BEST TOLERANCE and WIDEST THERAPEUTIC INDEX
What is the trend in terms of itraconazole?
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.
Azoles undergo what form of metabolism?
Hepatic
Interact with concurrent drugs metabolized via CYP2C9, CYP2C19 and CYP3A4
Which of the fungal agents do not undergo hepatic metabolism?
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.
Amphotericin B
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
What is the comparable drug to Amphotericin B?
Nystatin
Toxicity prevents systemic administration. Must have topic application in treatment of candidiasis.
Azole MOA
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
Which azole drugs have poor solubility to penetrate into CSF?
Ketoconazole and Itraconazole
These drugs are substrates for P-gp located in the BBB
Which azole drugs should not be administered during pregnancy?
Fluconazole and Voriconazole
Ketoconazole
- 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)
Voriconazole
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
What is the only azole with activity against mucormycosis?
Posaconazole
Orally administered; CYP mediated drug-drug interactions
Some of the azole drugs are associated with what cardiac issues?
Pro-arrythomogenic events (i.e. cardiac arrythmia)
Flucytosine (5-FC) MOA and Adverse Effects
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
Terbinafine MOA and Adverse Effects
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
Capsofungin (Echinocandins) MOA and Adverse Effects
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
Griseofulvin MOA and Adverse Effects
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.
What are some notable drug interactions?
- Griseofulvin is a CYP3A4 inducer producing drug-drug interactions with reduced clinical activity of Warfarin, oral contraceptive agents, cyclosporine
- Ketoconazole and warfarin
What are the classical mechanisms of resistance?
- Modification of drug target (e.g. Amphotericin B)
- Down-regulation of activation pathways or upregulation of protective mechanisms (e.g. azoles, flucytosine, capsofungin)
- Active energy-dependent efflux pumps remove toxic drug concentrations from within the cell
