Antifungals
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Questions and Answers

What is the alternate chemical name for nystatin?

  • Amphotericin B
  • Amphotericin A (correct)
  • Clotrimazole
  • Fluconazole

    • What is the mechanism of action (MOA) of nystatin?

  • Inhibits fungal cell wall synthesis
  • Disrupts fungal cell membrane permeability (correct)
  • Inhibits protein synthesis in fungi
  • Causes fungal DNA damage

    • Why is nystatin only a topical antifungal drug?

  • It is only effective against superficial fungal infections.
  • It has high toxicity when used systemically. (correct)
  • It is not effective for internal infections.
  • It is poorly absorbed in the gastrointestinal tract.

    • What antifungal is similar in structure to nystatin?

    <p>Amphotericin B</p> Signup and view all the answers

    Which antifungal drug is often the drug of choice to treat a disseminated or invasive fungal infection in an immunocompromised patient?

    <p>Amphotericin B</p> Signup and view all the answers

    Which of the following pairs is most correct regarding antifungal mechanisms?

    <p>Fluconazole --- binds to fungal CYP 450 enzymes</p> Signup and view all the answers

    What is the definition of 'tinea'?

    <p>A fungal infection of the skin</p> Signup and view all the answers

    Which antifungal drug functions by inhibiting CYP450 (14 alpha demethylase)?

    <p>Fluconazole</p> Signup and view all the answers

    Which statement about squalene epoxidase inhibition is correct?

    <p>It causes squalene accumulation, which is toxic.</p> Signup and view all the answers

    What is the primary action of echinocandins like caspofungin?

    <p>Inhibition of D-glucan synthesis</p> Signup and view all the answers

    Which of the following drugs works as a mitotic inhibitor by disrupting microtubules?

    <p>Griseofulvin</p> Signup and view all the answers

    What is a primary characteristic of the mechanism of action for flucytosine?

    <p>It is converted to an active compound by fungal enzymes.</p> Signup and view all the answers

    In what scenario is flucytosine primarily used in clinical practice?

    <p>In combination to avoid resistance in certain pathogens.</p> Signup and view all the answers

    What pharmacokinetic adjustment is necessary for flucytosine?

    <p>Decrease dosage in renal failure patients.</p> Signup and view all the answers

    Which of the following correctly describes how amphotericin B's formulations affect toxicity?

    <p>They decrease the binding of the drug to human cell membranes.</p> Signup and view all the answers

    What is the primary adverse effect associated with flucytosine when combined with amphotericin B?

    <p>Bone marrow toxicity.</p> Signup and view all the answers

    What mechanism do some fungi employ to resist flucytosine?

    <p>Altered phosphotransferase activity.</p> Signup and view all the answers

    Which of the following statements about the pharmacokinetics of flucytosine is accurate?

    <p>Normal dosage range is 100 - 150 mg/d/kg orally.</p> Signup and view all the answers

    What negative impact does flucytosine have on intestinal flora?

    <p>Biotransformation to a toxic compound, fluorouracil.</p> Signup and view all the answers

    What is the primary function of amphotericin B in treating fungal infections?

    <p>Forms pores in the cell walls of fungi</p> Signup and view all the answers

    Which of the following characteristics is unique to amphotericin B compared to nystatin?

    <p>Has a longer half-life</p> Signup and view all the answers

    What is the source organism for the production of nystatin?

    <p>Streptomyces noursei</p> Signup and view all the answers

    What is an adverse reaction commonly associated with intravenous administration of amphotericin B?

    <p>Fever and chills</p> Signup and view all the answers

    Which patient population is most likely to receive amphotericin B as a treatment option?

    <p>Patients with life-threatening mycotic infections</p> Signup and view all the answers

    What is the pharmacokinetic profile of amphotericin B regarding liver or kidney function?

    <p>No dose adjustment required regardless of function</p> Signup and view all the answers

    What is the major sterol that amphotericin B binds to in fungal cells?

    <p>Ergosterol</p> Signup and view all the answers

    How is amphotericin B typically administered?

    <p>Intravenously</p> Signup and view all the answers

    What is a key characteristic of azole antifungals in terms of mechanism of action?

    <p>Reduced synthesis of ergosterol by targeting fungal CYP 450 enzymes.</p> Signup and view all the answers

    Which azole drug is specifically known for lacking the specificity for fungal CYP 450 compared to human CYP 450?

    <p>Ketoconazole</p> Signup and view all the answers

    What type of infections are commonly treated with itraconazole and voriconazole?

    <p>Mycotic infections caused by Candida species and Aspergillus.</p> Signup and view all the answers

    What is a notable adverse effect associated with azole antifungals?

    <p>Minor gastrointestinal disturbances</p> Signup and view all the answers

    Which of the following statements accurately describes the pharmacokinetics of azole antifungals?

    <p>Pharmacokinetics vary widely between different azole drugs.</p> Signup and view all the answers

    What distinguishes echinocandins from azoles in terms of their structure?

    <p>They are synthetic cyclic peptides.</p> Signup and view all the answers

    Which antifungal agent currently has no reported mechanisms of resistance?

    <p>Caspofungin</p> Signup and view all the answers

    What is an important clinical consideration for azole antifungals concerning their interaction with human enzymes?

    <p>They inhibit human CYP450 to varying extents, leading to drug-drug interactions.</p> Signup and view all the answers

    Match each antifungal to its description

    <p>Ketoconazole = first azole antifungal with too many ADRs because of interaction with human CYP450 enzymes, no longer widely used if at all po but is available for use as a shampoo. Fluconazole = least effect on human CYP450 enzyme compared to all other azoles Posaconazole = PO only, broadest spectrum of all the azoles Itraconazole = used extensively for dermatophytoses and onychomycosis</p> Signup and view all the answers

    What is the mechanism of action (MOA) for echinocandins?

    <p>Disrupt fungal cell walls by inhibiting beta (1-3) glucan</p> Signup and view all the answers

    Which of the following are oral antifungals for mucocutaneous infections?

    <p>Griseofulvin</p> Signup and view all the answers

    What is the mechanism of action (MOA) for griseofulvin?

    <p>Deposits in newly forming skin where it binds to keratin, protecting the new skin from infection</p> Signup and view all the answers

    What is the mechanism of action (MOA) for terbinafine?

    <p>Inhibits fungal enzyme squalene epoxidase which blocks ergosterol synthesis, squalene builds up and is toxic to the fungus.</p> Signup and view all the answers

    Which of the following are topical antifungals? (Select all that apply)

    <p>Nystatin</p> Signup and view all the answers

    Flucytosine is non-water soluble.

    <p>False</p> Signup and view all the answers

    Which azole has the strongest interaction with CYP450?

    <p>Voriconazole</p> Signup and view all the answers

    Study Notes

    History of Nystatin

    • E.L Hazen discovered a Streptomyces bacterium in the soil of Walter B. Nourses' garden in 1948
    • Hazen named the bacterium Streptomyces noursei
    • It took 14 years for penicillin to be ready for human use, because of the need to grow the bacterium in sufficient quantity, extract the active agent from the media, identify, purify and test the active agent
    • Hazen grew cultures of Streptomyces noursei and then sent the broth to Rachel Brown in Albany, NY, for chemical isolation
    • Hundreds of Mason jars were shipped by USPS without any breakage or losses
    • In 1950, the drug was called nystatin (New York State Division of Laboratories)
    • The drug was approved by the FDA in 1954
    • Hazen and Brown held the patent for the drug in 1957
    • Nystatin forms pores in the cell walls of fungi

    Systemic Antifungal Drugs

    Amphotericin B

    • Isolated from Streptomyces nodosus
    • It is a non-water soluble amphoteric polyene macrolide
    • Amphotericin B has 7 double bonds in its structure, compared to 6 in Nystatin A
    • Amphotericin B binds to Ergosterol, a sterol found only in fungal cell walls
    • Cholesterol is the major sterol found in human and bacterial cells
    • The drug forms an open pore in the fungal cell wall, making ions leak out of the cell and causing cell death
    • Amphotericin B is only administered intravenously
    • It has a half-life of 15 days
    • It is slowly metabolized and does not require dose adjustment for hepatic or renal impairment
    • Amphotericin B has a broad spectrum of activity, and is effective against various yeast species, including:
      • Candida albicans
      • Cryptococcus neoformans
    • It is the drug of choice for all life-threatening mycotic infections
    • IV dose dependent adverse effects include: fever, chills, muscle spasms, vomiting, hypertension
    • Slower induction can cause renal damage
    • Amphotericin B liposome and other lipid-bound formulations decrease the binding of the drug to human cell membranes, thus lowering toxicity
    • Mechanism of resistance includes:
      • Decreasing drug binding to ergosterol by decreasing membrane concentration of ergosterol
      • Reducing the binding affinity of ergosterol for the drug

    Flucytosine

    • Flucytosine is a water-soluble synthetic pyrimidine analogue
    • Fungal intracellular enzymes convert flucytosine to a phosphorylated active compound
    • The phosphorylated analogue inhibits DNA and RNA synthesis
    • Human cells are unable to phosphorylate flucytosine
    • Flucytosine dose is 100 - 150 mg/d/kg orally
    • Dose adjustment is required for renal failure
    • Concentrations should be monitored to maintain levels of 50 - 100 ug/mL to avoid toxicity and ensure efficacy
    • Flucytosine possesses a narrow range of activity and is clinically effective against:
      • Cryptococcus neoformans
      • Some Candida species
    • It is only used in combination with other drugs to avoid resistance
    • Adverse effects can include: Intestinal flora biotransformation of the drug into the toxic antineoplastic drug, fluorouracil
    • Bone marrow toxicity is a risk, especially when combined with amphotericin B
    • Mechanism of resistance includes: altered (reduced) metabolism (phosphorylation) of the drug, common in monotherapy

    Azoles

    • Synthesized imidazoles and triazoles
    • Examples include:
      • Ketoconazole
      • Fluconazole
    • They reduce fungal synthesis of ergosterol by inhibiting fungal CYP 450 enzymes
    • Specificity is achieved through the drug’s greater affinity for fungal CYP450 compared to human CYP 450
    • Ketoconazole lacks this specificity and is no longer used except as a topical
    • Pharmacokinetics varies widely between the various azole drugs
    • Azoles have a broad range spectrum of activity
    • Clinical uses include:
      • Many Candida species
      • Endemic mycoses
      • Dermatophytes
      • Aspergillus (itraconazole and voriconazole)
    • Relatively non-toxic, with minor GI disturbances
    • All may induce abnormal liver function
    • All inhibit human CYP450 to some extent and cause drug-drug interactions
    • Mechanism of resistance includes:
      • Multiple mechanisms with ever increasing frequency
      • Imidazoles: ketoconazole, miconazole, clotrimazole
      • Triazoles: itraconazole, fluconazole, voriconazole, posaconazole

    Echinocandins

    • Synthetic cyclic peptides
    • Examples include:
      • Caspofungin (Cancidas®)
      • Micafungin
      • Anidulafungin
    • Inhibit the synthesis of beta (1,3)-D glucan in fungal cell walls, an essential component of the fungal cell wall
    • They do not interfere with human cell wall biosynthesis or function
    • They are administered intravenously
    • Have a long half life allowing for once a day dosing
    • They are effective against Candida species and the Aspergillus species
    • Adverse effects predominantly mild GI disturbances

    Topical Antifungal Agents

    • Nystatin (world’s first antifungal)
    • Topical azoles: clotrimazole, miconazole
    • Topical Allylamines: terbinafine, naftifine

    Summary of Drug Mechanisms

    Polyenes (amphotericin B)

    • Binds to ergosterol in cell wall
    • Cell wall develops pores, leaks, and cell lysis occurs

    Azoles (ketoconazole, fluconazole etc)

    • Inhibits CYP450 (14 alpha demethylase)
    • Decreases ergosterol production
    • Weak cell walls develop leading to leaks and cell lysis

    Echinocandins (caspofungin)

    • Inhibits D-glucan synthesis
    • Cell wall becomes weak causing leaks and cell lysis

    DNA or Protein Synthesis (flucytosine)

    • Flucytosine is metabolized to 5-flucytosine
    • 5-flucytosine is incorporated into fungal RNA and protein synthesis is stopped

    Squalene epoxidase inhibitor (terbinafine)

    • Inhibits squalene epoxidase enzyme
    • Squalene accumulates, which is toxic to the fungal cell

    Mitotic Inhibitor (griseofulvin)

    • Binds to new keratin in skin
    • Blocks new infection by inhibiting fungal mitosis through microtubule disruption

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