Microbiology pharm – Antifungals

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HY points about each drug followed by a quiz at the end

—

-Azoles (e.g., fluconazole, itraconazole, ketoconazole)

MOA of -azoles? (HY for Step 1)

• Inhibit ergosterol synthesis by inhibiting 14-demethylase.
• Ergosterol is the fungal equivalent of cholesterol.

HY uses for -azoles:

• Tinea corporis (ringworm) –> answer = topical -azoles (i.e., clotrimazole or miconazole).
• Candidal skin infections –> answer = oral fluconazole.
• Candidal esophagitis –> answer = oral fluconazole (in contrast, oropharyngeal candidiasis –> answer = nystatin mouthwash).
• Vaginal candidiasis –> answer = topical nystatin; if not effective, then oral fluconazole.
• Uncomplicated non-Pneumocystis fungal pneumonias (i.e., coccidioides, histoplasmosis, blastomycosis, mucormycosis, etc.) –> answer = oral fluconazole.
  • If the patient has rigors/chills, the answer is instead amphotericin B (rigors imply fungemia + dissemination –> need hard-hitting amphotericin B).
  • Some literature suggests that very mild fungal pneumonias can be observed rather than necessitating -azole Tx, but on the USMLE, always treat.
  • Prophylaxis and Tx for Pneumocystis jirovecii pneumonia is TMP/SMX.
• Cryptococcal neoformans meningitis –> answer = amphotericin B + flucytosine, then do a fluconazole taper for one-year (yes, one year).
• Tinea pedis (athletes’ foot) –> topical terbinafine or topical -azoles.
  • I’ve seen both as answers, but the USMLE won’t list both at the same time. In a vacuum, first-line is classically topical terbinafine, but yes, topical -azole is also correct.
• Sporothrix schenkii –> answer = oral itraconazole.
• Seborrheic dermatitis –> answer = ketoconazole or selenium shampoo (both are acceptable).
  • Seborrheic dermatitis presents as weeping papules along the hair lines + scaling of the scalp; in contrast, tinea capitis is classically described as a round-ish area of alopecia + scaling.
• Invasive/disseminated aspergillosis –> answer = IV caspofungin or IV voriconazole.

HY side-effects of -azoles:

• Hepatotoxicity.
  • Mild transaminitis (↑ LFTs) is normal and expected; do not discontinue or decrease dose if LFTs go up slightly.
  • Risk for hepatotoxicity is why topical nystatin is used before oral fluconazole for vaginal candidiasis. Because the proper medicine is to technically check the patient’s LFTs first if commencing -azoles, whereas topical nystatin can be used right away.
• Oral ketoconazole causes gynecomastia.
  • Ketoconazole is an antagonist at androgen receptors + blocks desmolase.
• Oral ketoconazole inhibits P-450 enzymes.
• Voriconazole causes arrhythmia.

Terbinafine

MOA of terbinafine? (HY for Step 1)

• Inhibits lanosterol synthesis by inhibiting squalene epoxidase.

When is terbinafine the answer?

• Onychomycosis (fungal infection of nails) –> answer = oral terbinafine.
  • You do not need to know doses or durations of Tx, but fun fact: for fingernails, give oral terbinafine for 6 weeks; for toenails, 12 weeks.
• Tinea pedis –> topical terbinafine (i.e., foams, sprays). Topical -azole is also acceptable and sometimes an answer (USMLE will not list both, don’t worry), but in a vacuum, topical terbinafine is first-line for athletes’ foot.

Toxicity of terbinafine?

• Hepatotoxicity.
  • Same as -azoles.
  • Check LFTs before commencing.
  • Mild transaminitis (↑ LFTs) is normal and expected; do not discontinue or decrease dose if LFTs go up slightly.

Griseofulvin

MOA of griseofulvin? (HY for Step 1)

• Inhibits microtubules.
  • USMLE also wants you to know the drugs that relate to microtubules:
    • Prevent assembly/formation of microtubules: 
      • Vinblastine
      • Vincristine
      • Colchicine
      • -Bendazoles (i.e., mebendazole, albendazole), which are anti-helminthic agents; do not confuse with -azoles.
      • Griseofulvin
    • Hyper-stabilize microtubules / prevent microtubule disassembly:
      • Taxanes (i.e., paclitaxel, docetaxel) –> odd one out, because the others all inhibit assembly/formation of microtubules, whereas taxanes hyper-stabilize / prevent disassembly.

When is griseofulvin the answer?

• Tinea capitis (cradle cap; scalp infection) –> answer = oral griseofulvin for patient only (i.e., do not give to close contacts; this is on an NBME).

Nystatin

MOA of nystatin?

• Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.
• Amphotericin B and natamycin have same MOA.

When is nystatin the answer?

• Vaginal candidiasis –> topical nystatin is used first; if ineffective, go to oral fluconazole.
• Oropharyngeal candidiasis –> nystatin mouthwash (not swallowed).
  • Should be noted that esophageal candidiasis is treated with oral fluconazole, not nystatin mouthwash.

Adverse effects of nystatin?

• Diarrhea, abdominal pain if consumed orally.

Natamycin

MOA of natamycin?

• Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.
• Amphotericin B and nystatin have same MOA.

When is natamycin the answer?

• Fungal infections in or around the eye.
• Used as eyedrops.

Amphotericin B

MOA of amphotericin B?

• Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.
• Nystatin and natamycin have same MOA.

Most important point to note about amphotericin B?

• Hard-hitting antifungal used for CNS or disseminated infections.
• Often used last resort.
• Wrong answer for uncomplicated fungal infections outside the CNS.

When is amphotericin B the answer?

• CNS infections (Cryptococcus neoformans meningitis) –> amphotericin B + flucytosine, followed by a one-year fluconazole taper.
• Disseminated fungal infections (i.e., disseminated histoplasmosis, blastomycosis, etc.).
• Fungemia (fungus in the blood) –> patient will have rigors/chills + high fever.
  • For example, on USMLE if a patient has a simple fungal pneumonia, answer = oral fluconazole. But if patient has fungal pneumonia + rigors/chills + fever of 103F, answer = amphotericin B, not fluconazole.
• Fungal sepsis –> SIRS + fungal infection.
  • SIRS = 2 or more of the following: temp <36C or >38C; HR >90; RR >20; WBCs <4,000 or >12,000.

Side-effects of amphotericin B?

• “Amphoterrible” –> hypersensitivity-like reaction with headache, chills, and fever (“shake and bake”).
• Hypokalemia + hypomagnesemia –> electrolyte disturbances due to renal wasting.

How to decrease risk of amphotericin B toxicity?

• Liposomal formulation –> slower intravascular release.

Echinocandins (caspofungin, micafungin)

MOA of echinocandins?

• Inhibit 1-3-ß-D-glucan synthase –> disrupts synthesis of cell wall.
  • Cell membrane, in contrast, refers to amphotericin B, nystatin, and natamycin (ionophores).

When is caspofungin the answer?

• Notably invasive candidemia or invasive aspergillosis.
• Amphotericin B can also treat these conditions. USMLE will not list both at the same time.

Flucytosine

MOA of flucytosine?

• Fluorinated pyrimidine analogue that disrupts both RNA and DNA synthesis.

When is flucytosine the answer?

• Not an answer on its own.
• Important point is that it is combined with amphotericin B when treating Cryptococcus neoformans meningitis.
  • Amphotericin B + flucocytosine, followed by a fluconazole taper for one year.

—

1. MOA of -azoles? (e.g., fluconazole, itraconazole, ketoconazole)

Inhibit ergosterol synthesis by inhibiting 14-demethylase.

Ergosterol is the fungal equivalent of cholesterol.

 

2. How do we treat tinea corporis (ringworm)? Be specific.

Topical -azoles (i.e., clotrimazole or miconazole).

3. 32F + obese + type II diabetic + 8×12-cm moist, red, elliptical, slightly itchy plaque under her left breast. Tx?

Candidal skin infections –> answer = treat with oral fluconazole.

4. 29M + HIV-positive + odynophagia; Most likely Tx?

Odynophagia in an immunocompromised patient is candidal esophagitis until proven otherwise. Treat with oral fluconazole.

Don’t confuse this with oropharyngeal candidiasis, which is treated with nystatin mouthwash.

Painful swallowing in immunocompromised patient requires endoscopy:

White plaques = candida = oral fluconazole.

Punched-out ulcers = HSV1/2 = oral acyclovir.

Linear / confluent ulcers = CMV = oral ganciclovir.

5. 40F + thick, white, curd-like discharge per vaginum. Treatment?

Vaginal candidiasis –> answer = topical nystatin; if not effective, then oral fluconazole.

6. 45M + farmer + lives in New Mexico + fever of 101F + patchy infiltrate seen on CXR + bronchoalveolar lavage shows spherules filled with endospores. Treatment?

Coccidioidomycosis –> classically seen in southwest US, with increased risk in those exposed to dust (i.e., recent earthquakes, farm workers).

Light microscopy shows spherules filled with endospores.

Treat uncomplicated fungal pneumonia with oral fluconazole.

Same goes for histoplasmosis, blastomycosis, etc.

If complicated (septic), patient gets amphotericin B.

Some literature suggests mild fungal pneumonias can be observed in immunocompetent patients. However on USMLE the answer is oral fluconazole.

Oral itraconazole is used for sporotrichosis.

TMP/SMX is used as prophylaxis for and treatment of Pneumocystis pneumonia.

7. 67M + works at plastics factory + sometimes eats lunch in nearby park where there are pigeons + history of Hodgkin disease + fever of 103F + has chills + blood culture shows yeast demonstrating broad-based budding. Dx + Tx?

Broad-based budding = blastomycosis.

Fungemia is evidenced by high fever + rigors/chills.

Treat fungemia, disseminated fungal infections, and CNS fungal infections with amphotericin B.

Hx of Hodgkin disease means patient is immunocompromised and susceptible to fungal infections.

8. 23M + IV drug user + fever of 104F + stiff neck + photophobia + latex agglutination assay and India ink prep of the CNS confirm the diagnosis. What’s the treatment?

Cryptococcal meningitis is diagnosed with latex agglutination (most accurate) of the CSF. This is the correct answer over India ink prep or mucicarmine staining.

Treat with amphotericin B + flucytosine, followed by a one-year taper of fluconazole. If you’re forced to choose one drug, choose amphotericin B.

9. 22M + plays football + itchy, scaly toes. Treatment? (Drug + route of administration)

Tinea pedis –> topical terbinafine (i.e., foams, sprays).

Topical -azole is also acceptable and sometimes an answer (USMLE will not list both, don’t worry), but if you’re forced to choose, topical terbinafine is first-line for athletes’ foot.

Oral terbinafine is for onychomycosis (nailbed fungus).

10. 38F + gardener + papule on the finger + red streaks seen on arm tracking to the axilla. Dx + Tx?

Sporothrix schenkii (sporotrichosis) –> give oral itraconazole.

Classically spreads lymphotogenously (lymphocutaneous sporotrichosis).

11. 59M + weeping papules in hairline + scaling of skin of the scalp and hairline + itchy; Dx + Tx?

Seborrheic dermatitis –> answer = ketoconazole or selenium shampoo (both are acceptable).

Seborrheic dermatitis presents as weeping papules along the hair lines + scaling of the scalp.

In contrast, tinea capitis is classically described as a round-ish area of alopecia + scaling.

12. 55F + recently treated with chemo for breast cancer + fever of 103F + chills + blood culture shows 45-degree branched septate hyphae. Dx + Tx?

45-degree branched septate hyphae = aspergillosis (90-degree branched hyphae = mucormycosis).

Invasive / disseminated aspergillosis (as evidenced by the high fever and rigors/chills + positive blood culture) is treated with amphotericin B or an echinocandin, such as caspofungin or micafungin.

Echinocandins classically treat invasive asperillosis and invasive candidemia. But amphotericin B is perfectly acceptable.

Bottom line: if you get a disseminated aspergillus or candida infection and amphotericin B isn’t listed, choose the echinocandin.

 

13. Name four HY side-effects of -azoles (e.g., fluconazole, ketoconazole, etc.).

Hepatotoxicity.

• Mild transaminitis (↑ LFTs) is normal and expected; do not discontinue or decrease dose if LFTs go up slightly.
• Risk for hepatotoxicity is why topical nystatin is used before oral fluconazole for vaginal candidiasis. Because the proper medicine is to technically check the patient’s LFTs first if commencing -azoles, whereas topical nystatin can be used right away.

Oral ketoconazole causes gynecomastia.

• Ketoconazole is an antagonist at androgen receptors + blocks desmolase.

Oral ketoconazole inhibits P-450 enzymes.

Voriconazole causes arrhythmia.

14. MOA of terbinafine?

Inhibits lanosterol synthesis by inhibiting squalene epoxidase.

15. Name two important uses for terbinafine.

Onychomycosis (fungal infection of nails) –> answer = oral terbinafine.

• You do not need to know doses or durations of Tx, but fun fact: for fingernails, give oral terbinafine for 6 weeks; for toenails, 12 weeks.

Tinea pedis –> topical terbinafine (i.e., foams, sprays). Topical -azole is also acceptable and sometimes an answer (USMLE will not list both, don’t worry), but in a vacuum, topical terbinafine is first-line for athletes’ foot.

16. Most important toxicity of terbinafine?

Hepatotoxicity.

• • Same as -azoles.
  • Check LFTs before commencing.
  • Mild transaminitis (↑ LFTs) is normal and expected; do not discontinue or decrease dose if LFTs go up slightly.

17. a) MOA of griseofulvin?

b) Any other drugs with similar MOA?

Inhibits microtubules.

USMLE also wants you to know the other drugs that relate to microtubules:

• Prevent assembly/formation of microtubules: 
  • Vinblastine
  •  Vincristine
  •  Colchicine
  • -Bendazoles (i.e., mebendazole, albendazole), which are anti-helminthic agents; do not confuse with -azoles.
  •  Griseofulvin

• Hyper-stabilize microtubules / prevent microtubule disassembly:
  • Taxanes (i.e., paclitaxel, docetaxel) –> odd one out, because the others all inhibit assembly/formation of microtubules, whereas taxanes hyper-stabilize / prevent disassembly.

18. Highest yield use for griseofulvin on USMLE?

Tinea capitis (cradle cap; scalp infection) –> answer = oral griseofulvin for patient only (i.e., do not give to close contacts; this is on an NBME).

 

19. a) MOA of nystatin?

b) Any drugs with similar MOA?

a) Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.

b) Amphotericin B and natamycin have same MOA.

20. What are the two highest yield uses for nystatin on the USMLE.

Vaginal candidiasis –> topical nystatin is used first; if ineffective, go to oral fluconazole.

Oropharyngeal candidiasis –> nystatin mouthwash (not swallowed).

• Should be noted that esophageal candidiasis is treated with oral fluconazole, not nystatin mouthwash.

21. Adverse effects of nystatin?

Notably diarrhea and abdominal pain if consumed orally.

22. a) MOA of natamycin?

b) Any other drugs with similar MOA?

a) Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.

b) Amphotericin B and nystatin have same MOA.

23. When is natamycin the answer?

Fungal infections in or around the eye.

Used as eyedrops.

Same MOA as nystatin and amphotericin B (ionophore –> pores in cell membrane).

24. a) MOA of amphotericin B?

b) Any other drugs with similar MOA?

a) Ionophore – i.e., binds to ergosterol in the fungal cell membrane and forms pores/holes.

b) Nystatin and natamycin have same MOA.

25. Name four HY uses for amphotericin B on the USMLE.

CNS infections (Cryptococcus neoformans meningitis) –> amphotericin B + flucytosine, followed by a one-year fluconazole taper.

Disseminated fungal infections (i.e., disseminated histoplasmosis, blastomycosis, etc.).

Fungemia (fungus in the blood) –> patient will have rigors/chills + high fever.

• For example, on USMLE if a patient has a simple fungal pneumonia, answer = oral fluconazole. But if patient has fungal pneumonia + rigors/chills + fever of 103F, answer = amphotericin B, not fluconazole.

Fungal sepsis –> SIRS + fungal infection.

• SIRS = 2 or more of the following: temp <36C or >38C; HR >90; RR >20; WBCs <4,000 or >12,000.

26. Name two HY side-effects of amphotericin B for USMLE.

“Amphoterrible” –> hypersensitivity-like reaction with headache, chills, and fever (“shake and bake”).

Hypokalemia + hypomagnesemia –> electrolyte disturbances due to renal wasting.

27. How to decrease risk of amphotericin B toxicity?

Liposomal formulation –> slower intravascular release.

28. MOA of echinocandins? (caspofungin, micafungin)

Inhibit 1-3-ß-D-glucan synthase –> disrupts synthesis of cell wall.

• Cell membrane, in contrast, refers to amphotericin B, nystatin, and natamycin (ionophores).

29. When is caspofungin the answer?

Notably invasive candidemia or invasive aspergillosis.

Amphotericin B can also treat these conditions. USMLE will not list both at the same time.

30. a) MOA of flucytosine?

b) When is it the answer?

a)

Fluorinated pyrimidine analogue that disrupts both RNA and DNA synthesis.

b)

• Not an answer on its own.
• Important point is that it is combined with amphotericin B when treating Cryptococcus neoformans meningitis.
• • Amphotericin B + flucocytosine, followed by a fluconazole taper for one year.

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