Antifungals

Question 1

ANTIFUNGAL DRUGS CLASSIFIED BY MOA

Answer 1

• Drugs that alter cell membrane permeability: Polyenes, Azoles, Allylamines
• Drugs that block nucleic acid synthesis: Flucytosine
• Drugs that disrupt microtubule function: Griseofulvin
• Drugs that disrupt the fungal cell wall: Echinocandins

Question 2

SYSTEMIC DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOSES

Answer 2

• Amphotericin B
• Flucytosine
• Azoles
• Echinocandins

Question 3

AMPHOTERICIN B

Answer 3

• Polyene antibiotic.
• Antifungal agent with the broadest spectrum of action.
• It has activity against the clinically significant yeasts, the organisms causing endemic mycoses, and the pathogenic molds.
• Often used as initial induction regimen to rapidly reduce fungal burden.
• Then patients continue therapy with an azole.

**MOA: **Amphotericin B binds to ergosterol, forming pores in the cell membrane. The pores allow leakage of intracellular ions and macromolecules, leading to cell death.

**Indications: **Cryptococcus

PK

• Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
• Poorly absorbed from the GI tract.
• Must be given IV (slow infusion).
• Penetration into the CSF is extremely low.
• Intrathecal therapy may be necessary for meningeal disease.
• Amphotericin B is the preferred treatment for deep fungal infections during pregnancy.

Question 4

AMPHOTERICIN B: ADVERSE EFFECTS

Answer 4

INFUSION-RELATED TOXICITY

• Nearly universal. Fever and chills, muscle spasms, vomiting, headache and hypotension.
• Can be attenuated by slowing infusion rate or decreasing daily dose for 2 wk
• Pre-medication with antihistamines, glucocorticoids, antipyretics or meperidine can be helpful.

SLOWER TOXICITY

• Amphotericin B also binds to cholesterol and forms pores in mammalian cell membranes, leading to renal toxicity.
• Renal impairment occurs in nearly all patients.
• Renal damage can be attenuated with sodium loading: it is common practice to administer saline infusion with amphotericin B.
• Hypochromic normocytic anemia, due to reduced EPO production.
• advisable to monitor liver function, serum electrolytes (particularly magnesium and potassium), blood counts, and hemoglobin.
• Intrathecal administration can cause seizures and serious neurological damage.

Pregnancy

• Induction should be performed with Amphotericin B (pregnancy category B) with or without flucytosine.

Question 5

AMPHOTERICIN B: LIPID FORMULATIONS

Answer 5

• Liposomal amphotericin B (L-AMB)
• Amphotericin B lipid complex (ABLC)
• Amphotericin B colloidal dispersion (ABCD)
• Nephrotoxicity is less common and less severe with the lipid formulations.

Question 6

FLUCYTOSINE including Adverse

Answer 6

Synthetic pyrimidine antimetabolite.

Taken by fungal cells via the enzyme cytosine permease.

Converted first to 5- FU and then to 5-fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase, thus blocking synthesis of dTMP -> suicide inhibitor

MOA:

• 5-FUTP is also formed, which inhibits protein synthesis
• Mammalian cells are unable to convert the parent drug to its active metabolites.
• Combination of flucytosine and amphotericin B is synergistic.

Uses

• Indicated only for serious infections caused by susceptible strains of Candida and/or Cryptococcus.
• Should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis in order to avoid resistance.

Adverse:

• Bone marrow toxicity is the most common.
• Flucytosine is a category C drug for pregnancy, and therefore, its use must be considered in relationship to benefit versus risk. Fluconazole (pregnancy category C)

Question 7

AZOLES including adverse

Answer 7

• Relatively nontoxic oral drugs.
• Important role in systemic therapy.
• Classified as imidazoles or triazoles.

Imidazoles

• Ketoconazole
• Miconazole
• Clotrimazole

Triazoles

• Itraconazole
• Fluconazole
• Voriconazole
• Posaconazole

MOA

• Azoles inhibit the 14-alpha-demethylase converting of lanosterol to ergosterol
• This disrupts membrane function and increases permeability.
• Specificity of azole drugs results from their greater affinity for fungal than for human P450 enzymes.
• Triazoles are more specific than imidazoles.

Adverse

• Relatively nontoxic.
• Most common adverse reaction: minor GI upset.

Question 8

Ketoconazole

Answer 8

• Strong inhibitor of 3A4
• Can decrease plasma testosterone levels and cause gynecomastia, decreased libido and loss of potency in men and menstrual irregularities in women.
• High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations.
• Best absorbed at low gastric pH:antacids,H2 blockers or proton pump inhibitors interfere with absorption of ketoconazole.
• Poor penetration in the CSF.

Uses

• Due to its narrow spectrum and adverse effects ketoconazole is rarely used for systemic mycoses.
• Still used for superficial mycoses.

Question 9

FLUCONAZOLE

Answer 9

• Good CSF penetration.
• High oral bioavailability.
• Available in oral and IV formulations.
• Moderate inhibitor of CYP3A4.
• Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin.

Uses

• DOC in esophageal, oropharyngeal, vulvovaginal or urinary candidiasis.
• DOC for candidemia.
• DOC for coccidioidomycosis. ​
• DOC for consolidation and maintenance therapy of cryptococcal meningitis after induction with amphotericin B.
• Alternative to amphotericin B for non-severe criptococcal meningitis.
• **DOC for initial and secondary prophylaxis against cryptoccocal meningitis. **
• Ineffective against Aspergillus or other filamentous fungi.

**PK: **

• highly water soluble so highly absorable (CSF: serum conc ratio > 0.7)
• renal excretion

Question 10

ITRACONAZOLE

Answer 10

• Metabolized primarily by CYP3A4.
• Strong inhibitor of CYP3A4. May cause potentially fatal arrhythmias when given concurrently with cisapride or quinidine.
• Poor bioavailability.
• Penetrates poorly in CSF.
• Absorption reduced by antacids, H2 blockers and proton pump inhibitors.

Uses

• Preferred azole for mycoses due to the dimorphic fungi Blastomyces, Sporothrix and Histoplasma.
• Effective against Aspergillus, but has been replaced by voriconazole for this indication.

Used for dermatophytoses and onychomycosis.

Question 11

VORICONAZOLE

Answer 11

• Spectrum similar to itraconazole.
• DOC for invasive aspergillosis.
• Transient visual disturbances occur inupto30% of patients.
• Voriconazole is metabolized by and inhibits CYP2C19, CYP2C9 and CYP3A4.
• The significant number of drug interactions due to its metabolism through the various hepatic enzymes may limit its use.

Question 12

POSACONAZOLE

Answer 12

• Spectrum similar to itraconazole, but it has activity against Zygomycetes such as Mucor.
• Inhibits CYP3A4.

Question 13

ECHINOCANDINS: CASPOFUNGIN

Answer 13

• Large cyclic peptides linked to a long-chain fatty acid.
• Active against candida and aspergillus but not Cryptococcus neoformans.
• **Only available IV. **
• Inhibit synthesis of Beta (1-3)-D-glucans in the fungal cell wall.
• This results in disruption of the fungal cell wall and cell death.

Question 14

SYSTEMIC DRUGS FOR SUPERFICIAL MYCOSES

Answer 14

• Griseofulvin
• Terbinafine
• Ketoconazole
• Fluconazole
• Itraconazole

Question 15

GRISEOFULVIN including adverse

Answer 15

• Only use: treatment of dermatophytosis.
• Absorption improved when given with fatty foods.

**MOA: **Disrupts mitotic spindle and inhibits mitosis.

**Uses: **Severe dermatophytoses of the skin,hair,and nails.

Adverse: Induces P450 enzymes: increases metabolism of a number of drugs, including warfarin.

Question 16

TERBINAFINE

Answer 16

Allylamine.
Available in oral formulation.

MOA

• Inhibition of squalene epoxidase prevents synthesis of ergosterol.
• It also causes accumulation of toxic levels of squalene in the fungal cell.

**Uses: **effective in onychomycosis.

Question 17

TERBINAFINE: ADVERSE EFFECTS

Answer 17

• GIupsets, rash, headache, taste disturbances.
• Terbinafine doesn’t affect the P450 system -> no drug interactions.

Question 18

TOPICAL DRUGS FOR SUPERFICIAL MYCOSES

Answer 18

• Nystatin
• Amphotericin B
• Clotrimazole
• Miconazole
• Ketoconazole
• Terbinafine
• 2 azoles most commonly used topically are clotrimazole and miconazole.

Question 19

Nystatin

Answer 19

• Polyenemacrolide.
• Structurally similar to amphotericin B.
• Same mechanism of action.
• Too toxic for IV administration. Not absorbed from the GI tract, skin, or vagina.

**Uses: only for candidiasis. **

Question 20

PCP therapy

Answer 20

DOC: co-trimoxazole aka TMP-SMX

• Trimethoprim exerts a synergistic effect with sulfonamides.

Alternative therapies are:

• Clindamycin + primaquine
• Dapsone + trimethoprim
• Atovaquone
• Pentamidine
• Patients with moderate-to-severe disease should also be given prednisone (room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg).

Question 21

TMP-SMX - Adverse

Answer 21

High- dose therapy entails significant toxicity, especially in patients with AIDS. Adverse effects include:

• Erythematous, maculopapular, morbilliform rash and, less commonly, severe urticaria, exfoliative dermatitis, and Stevens-Johnson syndrome.
• GI intolerance (nausea, vomiting, abdominal pain) is common.
• Hematologic side effects may include leukopenia, anemia, and/or thrombocytopenia.
• Neurologic toxicities and hepatitis also may occur.

Question 22

Opportunistic infections may appear in HIV-infected Pt according to CD4+ count

Answer 22

The risk for specific opportunistic infections varies with the degree of immunosuppression.

• Asymptomatic patients with moderate immunosuppression (CD4+ counts 200–500) may become infected with herpes viruses and Candida and/or develop pneumonias, enteric infections, and meningitis with common pathogens.
• A CD4+ count < 200 increases the risk for opportunistic pathogens (e.g., PCP), opportunistic tumors, wasting, and neurologic complications.
• With a CD4+ count of 50 to 100, invasive candidiasis, cerebral toxoplasmosis, cryptococcosis, and various protozoal infections are observed.
• When the CD4+ count falls below 50, the patient is in an advanced immunosuppressed state, which is associated with non-Hodgkin lymphoma (NHL), CMV, and disseminated Mycobacterium avium complex.

Question 23

Primary prophylaxis is strongly recommended in HIV Pt against which infections?

Answer 23

• Primary prophylaxis against PCP (TMP-SMX, one double-strength tablet daily, is the most efficacious prophylactic regimen; a single-strength tablet daily is less toxic and nearly as efficacious. ),
• Toxoplasmosis, Mycobacterium tuberculosis, MAC, and varicella-zoster virus (VZV).
• Vaccinations to prevent Streptococcus pneumoniae, hepatitis B virus, hepatitis A virus, and influenza virus infection generally are recommended for all HIV- infected patients.
• Primary prophylaxis for fungal infections (Cryptococcus neoformans and Histoplasma capsulatum), CMV, and bacterial infections are not routinely recommended for most patients, except in unusual circumstances.

Question 24

Secondary prophylaxis is strongly recommended in HIV+ Pt against which infections?

Answer 24

Strongly recommend secondary prophylaxis for PCP, toxoplasmosis, MAC, CMV, Salmonella species, and infections caused by endemic fungi and C. neoformans.