Pharmacotherapy of Antifungal Agents 1

Candida species general susceptibilities

Which candida species are pretty much resistant to everything?

• C. glabrata

  • susceptible to Flucytosine

• C. Krusei (Pichia kudriazevii)

Both are susceptible to Echinocandins tho!

What are the different fungal forms?

• Unicellular (yeasts)

  • Single cells, spherical, with rigid cell wall

• Filamentous (molds)

  • Filaments called hyphae; collectively called mycelium

  • Hyphae are septate (partitioned) or non-septate

• Dimorphism

  • May exist as yeast (>37 degrees C) or as mold

What are characteristics of yeasts?

• Round, oval, smooth appearing flat colonies that reproduce by budding

What are characteristics of molds?

• Fuzzy appearing, growth through branching

What are characteristics of dimorphic fungi?

• Can exist as yeast or mold depending on the environment

What are differences between bacteria and fungi?

• Bacteria

  • Resistance develops rapidly

• Fungi

  • Resistance is stable over time - species predicts susceptibility

What are systemic fungal species?

• Infections that invade the internal organs

• May be caused by primary pathogens or opportunistic pathogens (require debilitated host)

• Regardless of pathogen, infection is more marked and serious in immunocompromised hosts

• Systemic mycoses increasing because of more, and more highly immunocompromised patient populations (bone marrow and solid organ transplant, immunomodulatory therapy, etc)

What are some characteristics of Amphotericin B?

• Broadest spectrum agent covering:

  • Candida spp (but not super effect for C. lusitaniae)

  • Aspergillus (Except Aspergillus terreus)

  • Cryptococcus spp

  • Endemic fungi

  • Mucor

• Fungicidal

• No dose adjustments needed for renal/hepatic dysfunction

What are some adverse effects associated with Amphotericin B?

• Renal toxicity

• Electrolyte wasting (Mg, K)

• Infusion-related reactions first 3-5 days (fevers, chills, rigors, thrombophlebitis)

• Lipid formulations shown to have less renal toxicity compared to Ampho deoxycholate!!!

  • Liposomal amphotericin (Ambisone)

  • Lipid complex (Abelcet)

What are drug interactions with amphotericin B?

• Avoid with other nephrotoxic agents (tacro, cyclosporine, AGs)

• Digoxin: potential for hypokalemia

Amphotericin is the drug of choice for ____ in ____ patients:

Drug of choice for invasive candidiasis in pregnant patients!

What are the triazoles?

• ketoconazole (Nizoral®)

• itraconazole (Sporanox®)

• fluconazole (Diflucan®)

• voriconazole (Vfend®)

• posaconazole (Noxafil®)

• isavuconazole (Cresemba®)

What does Itraconazole (Sporanox) cover?

• Endemic fungi

• Candida spp with dose-dependent susceptibility or resistance to C. glabrata and C. krusei

• Aspergillus spp.

What are adverse effects of Itraconazole?

• Peripheral neuropathy

• N/V

• Increased LFTs (monitor LFTs with all -azoles)

• Hypokalemia

• Increased triglycerides

• Rash

• Negative inotropic effect

What is Itraconazole contraindicated with?

• STATINS!

  • Except Pravastatin

• CYP3A4 substrate and inhibitor (avoid PPIs and H2RA)

What’s special about the dosing of Itraconazole?

All formulations require a loading dose!

What does Fluconazole cover?

• Candida species EXCEPT

  • C. glabrata (dose-dependent)

  • C. krusei (Pichia kudriazevii)

• Cryptococcus

• Endemic fungi

What’s special about Fluconazole?

• The only -azole that has Renal dose adjustments

• Least likely to have DIs

• GOOD urinary penetration

What are adverse effects/monitoring of Fluconazole?

• Generally well tolerated

  • Some N/V, increased LFTs, HA, reversible alopecia

• Monitor: LFTs! rash, QT interval

• Pregnancy cat. C (ok to use one time dose)

What does Voriconazole cover? (what is the main use of Voriconazole)

• Drug of Choice for Aspergillus!

• Candida spp. (incl. C. krusei) with dose-dependent susceptibility or resistance to C. glabrata

• Fusarium spp. and Scedosporium spp.

What are adverse effects/monitoring/DIs of Voriconazole?

• AEs

  • Visual disturbances (phototopsia, hallucinations), hepatoxicity, skin rash

  • Photosensitivity

  • Prolonged QT interval & Torsades

  • Periostitis

• Monitor: LFTs, renal function, visual function

• Avoid IV formulation in patients with CrCl < 50 mL/min

What is one specific population Voriconazole is contraindicated in?

PREGNANCY!!!

What does Posaconazole cover?

• Candida spp. (incl. C. krusei) with dose-dependent susceptibility or resistance to C. glabrata

• Aspergillus spp.

• Mucor

• Endemic fungi

What is the random drug interaction Posaconazole has?

• Cyclosporine

  • It increases Cyclosporine levels so must decrease dose

What do we monitor in Posaconzole? Pregnancy?

• Monitor: LFTs, PO intake, diarrhea, K, Mg, Ca

• Pregnancy category C

What does Isavuconazole cover?

• Candida spp. Aspergillus spp. (second line1 )

• Cryptococcus, Scedosporium,

• Mucor,

• endemics

• Indicated for invasive aspergillosis and mucormycosis

What are AEs/DIs/monitoring of Isavuconazole?

• AEs

  • Nausea, hepatotoxicity, CNS effects (seizure)

• Drug interactions: CYP3A4

  • Rifampin, Atorvastatin, immunosuppressants

  • Mild P-gp inhibitor

• Monitor: LFTs, K, Mg

• Teratogenic and embryocidal

What are the echinocandins?

• anidulafungin (Eraxis®)

• micafungin (Mycamine®)

• caspofungin (Cancidas®)

• rezafungin (Rezzayo®)

• “All pretty much the same”

What do echinocandins cover?

• Primary role: Candida species

  • Including azoleresistant, variable activity against C. parapsilosis)

• Aspergillus

• Is fungicidal!!!

What are adverse effects/monitoring of Echinocandins?

• Increase in liver enzymes!!!

• Monitor: LFTs, CBC

• Distributes well to major organ sites

• Does not significantly penetrate urinary tract

What does Flucytosine (5-FC) cover?

• Primarily adjuvant therapy in cryptococcal meningitis

• Candida spp (Except c. krusei)

What is special about Flucytosine?

• Dosing adjustment is required for renal dysfunction!

• not given as monotherapy!

• Contraindicated in pregnancy!

What are adverse effects of Flucytosine?

• Rash, diarrhea

• Liver toxicity

• Hematologic toxicity (related to serum concentration >100 mg/L)

  • Can cause bone marrow suppression!

What is Ibrexafungerp (Brexafemme) used for? What’s special about it?

• Vulvovaginal candidiasis

• Contraindicated in pregnancy!