Anti- fungals

1. Anti-fungals Brought to you by: David S Shree P Patrick M Lauren W Lamar W Trisha K

2. Amphotericin B

3. Quick Review of Fungal Morphology Cell Membrane: Ergosterol (not cholesterol) Cell Wall: Carbs Proteins Capsule: Surrounds cell wall India Ink Staining Cryptococcus Neoformans

4. What is Amphotericin B? Antifungal Polyene What is it’s MOA? Bind Ergosterol Punches holes in the cell membrane How is it given? IV ONLY So why is it the Godfather? Useful for most systemic fungal infections Candida, Cryptococcal Meningitis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Invasive Aspergillosisand Sporotrichosis, Mucormycosis

5. Wait, Ketoconazole attacks Ergosterol, too…so, how are they different? Ketoconazole inhibits ergosterol synthesis NOT USED FOR SYSTEMIC FUNGAL INFECTIONS!!!

6. If Amphotericin B is so awesome,then why is it known as Amphoterrible or Awfultericin? Amphotericin B is renowned for it’s adverse effects: • Renal Toxicity • Reversible – follow BUN/Cr • Acute Febrile Reaction • Anemia • Phlebitis

7. What’s the easiest way to remember Amphotericin B? Think of Amphotericin as the “Amphibian Terrorist” IV drug delivery Fungicidal by blowing holes in the cell membrane Nephrotoxic

8. Nasty Nystatin– the bastard child MOA: Same as Amphotericin B Why so Nasty??? Too toxic for IV use Uses?? Skin and oral fungi “Swish and Swallow”

9. Azoles fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole

10. Mechanism of action • Inhibits fungal sterol (ergosterol) synthesis • What is ergosterol? • Ergosterol is a component of yeast and fungal membranes, not found in animals • How do azoles do this? • Inhibit Lanosterol 14 α-demethylase, the enzyme that converts lanosterol to ergosterol

11. Clinical Use of Azoles • Systemic mycoses • Fluconazole: cryptococcal meningitis in AIDS patients (why this azole specifically? • Candidal infections of all types • Ketoconazolefor Blastomyces, Coccidiodes, Histoplasma, Candida albicans • Hypercortisolism • Clotrimazole and miconazolefor topical fungal infections

12. Candida albicans • Systemic or superficial fungal infection • Dimorphic yeast with pseudohyphae & budding yeasts at 20°C • Germ tubes at 37°C • Oral and esophageal thrush in immunocompromised • Neonates • Steroids • Diabetes • Use of antibiotics • AIDS • Tx: fluconazoleor caspofungin • Vulvovaginitis • Diabetes • Use of antibiotics • Tx: topical azole • Diaper rash • Endocarditis • IV drug users • Disseminated candidiasis • To any organ • Tx: amphotericin B, fluconazole, or caspofungin • Chronic mucocutaneouscandidiasis

13. Histoplasma • Lab appearance • Oval yeast cells within macrophages • Immunocompetent patients • Pulmonary symptoms • Immunocompromised patients (i.e. AIDS patients) • Low-grade fevers • Cough • Hepatosplenomegaly • Tongue ulcers

14. Blastomyces • States east of Mississippi River and Central America • Inflammatory lung disease • Can disseminate to skin and bone • Forms granulomatous nodules • Broad-base budding (same size as RBC)

15. Coccidiodes • Southwestern US, California • Pneumonia and menigitis • Can disseminate to bone and skin • Case rate increases after earthquakes (spores in dust are thrown up in air and become spherules in lungs) • Spherule filled with endosphores (much larger than RBC)

16. Cryptococcus • Heavily encapsulated yeast • Not dimorphic • Cryptococcal meningitis, cryptococcosis • Found in soil, pigeon droppings • Acquired through inhalation with hematogenous dissemination • Culture on Sabourad’s agar • Stains with India ink • Stains with mucicarmine • Latex agglutination test detects polysaccharide capsular Ag and is more specific • “soap bubble” lesions in brain

17. Toxicity of Azoles • Hormone synthesis inhibition> gynecomastia (ketoconazole) • Liver dysfunction> inhibits cytochrome p450 • Fever • Chills

18. Flucytosine (5-fluorocytosine) • A fluorinated pyrimidine analogue • common brand name: Ancobon • Oral & injectable (in some countries)

19. Flucytosine Mechanisms of Action Taken up by susceptible fungal cells and converted to 5-flurouracil - inhibits fungal DNA synthesis

20. Spectrum of susceptible fungi and resistance • active in vitro as well as in vivo against some strains of Candida and Cryptococcus • Used incombination with amphotericin B and/or azole antifungals such as fluconazole or itraconazole • Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophila, and Phialophora • In different strains of Candida resistance has been noted to occur in 1-50% of all specimens obtained from patients

21. Flucytosine Side Effects • Renal function: Increased BUN and serum creatinine have been noted • crystalluria and acute renal failure have also been seen • Liver function: elevations of liver enzymes and bilirubin, hepatic dysfunction, jaundice andliver necrosis have all been seen • some fatal cases have been reported, however the majority of cases were reversible • GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitis • Antiproliferative actions on bone marrow and GI tissue • Bone marrow toxicity can be irreversible and may cause death, particular in immunocompromised patients

22. Side Effects Continued • Anaphylaxis • Adverse CNS effects are frequent and include confusion, hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo and sedation • Skin reactions: Rash, pruritus, and photosensitivity have all been noticed • toxic epidermal necrolysis (Lyell's syndrome) may also be encountered and may be life-threatening

23. You have invasive aspergillosis andAmphoteracin B didn’t work……. • You still have: • Fever, chills • Hemoptysis • Chest pain • Weight loss • and fungus balls….. Maybe not that big….

24. Caspofungin aka the Penicillin of Antifungals! • It is an echinocandin • Inhibits the synthesis of β (1,3)-D-glucan: a component of the fungal cell wal • Thus inhibiting cell wall synthesis

25. So on top of your symptoms: you now have to worry about these side effects: • Increased Transaminases • Septic shock • Rash • Increased AlkPhos • Anaphylaxis • Injection site reactions • Fever • Diarrhea • Hypotension

26. But don’t worry…..the only side effects that are really common are: • Flushing • GI upset

27. And on the plus side….. • If you happen to also have candidiasis that has also been resistant to other drugs……. • Caspofungin will treat that as well!

28. Question • A 25 year old lady who was diagnose with cancer walks into your office worried about her toe nails. She admits to going to the nail shop twice a month for pedicures and manicures. She also recalls having a minor cut near her cuticle before getting her last pedicure. You recognize it as onychomycosis. What is the mechanism of action of the drug you give to treat her condition?

29. Answer choices • A. Inhibits DNA synthesis by conversion to 5-fluorouracil • B. Inhibits the fungal enzyme squaleneepoxidase • C. Interferes with microtubule function; disrupts mitosis • D. Inhibits fungal sterol synthesis, by inhibiting the P-450 enzyme that converts lanosterol to ergosterol

30. Answer choices • A. Inhibits DNA synthesis by conversion to 5-fluorouracil--Flucytosine • B. Inhibits the fungal enzyme squaleneepoxidase--Terbinafine • C. Interferes with microtubule function; disrupts mitosis--Griseofulvin • D. Inhibits fungal sterol synthesis, by inhibiting the P-450 enzyme that converts lanosterol to ergosterol--Azoles

31. Terbinafine • Mechanism of Action: inhibits the fungal enzyme squaleneepoxidase • Clinical use: treats dermatophytes(especially onychomycosis—fungal infection of finger or toe nails) • Dermatophytes: Microsporum, **Trichophyton(T. rubrum), Epidermophyton • Infection of the skin • T. corporis (body) • T. cruris (groin) • T. pedis (feet) • Infection of the hair: T. capitis (scalp) • **Infection of the nail: T. unguium

32. How can you get it? • Fungal nails: normally from moist wet areas; for example, communal showers • Elderly people with an underlying disease state are at higher risk and people with autoimmune disorders or who are immunosuppressed • Diabetics

33. Griseofluvin • MOA: (First Aid Version) • Griseofulvininhibits fungal mitosis by targeting microtubules • By targeting microtubules, this disrupts the mitotic spindle resulting in inhibition of mitotic activity . X Griseofluvin acts intracellulary binding to fungal microtubules.

34. Griseofluvin • MOA: What’s also important to understand. • Griseofluvinbinds keratin in keratin precursor cells • As the drug accumulates in the skin, these cells become resistant to the fungal infection • Fungus is cleared as the Griseofluvin skin cells replace the old infected cells Grisofluvin binds to keratin containing cells. Accumulations seen in skin, hair, and nails.

35. Griseofluvin • Oral Agent used for SUPERFICIAL fungal infections • Inhibits the growth of: Dermatophytes (tinea and ringworm) • Dermatophytes • Pruritic lesions with central clearing resembling a ring • See mold hyphae on KOH, not dimorphic • Microsporum • Trichophyton • Epidermophyton

36. Dermatophytes • Tineacapitis(ringworm of the scalp) • Tineabarbae(barber’s itch) • Tineacorporis(ringworm of the body) • Tineacruris(ringworm of the thigh/groin) • Tineapedis(athlete’s foot) • Tineaunguium(onychomycosis; ringworm of the nails)

37. Griseofluvin Side Effects • Side Effects: • Confusion and Headaches • Increases P450 metabolism • Inhibits the action of Warfarin • Teratogenic • Carcinogenic Pregnancy P450 X

38. Antifungals Summary • Amphotericin B • Azoles • Flucytosine • Caspofungin • Terbinafine • Griseofluvin

39. Questions

40. Which of the following is a polyene antifungal agent used for many life threatening fungal infx? A. Amphotericin B B. Griseofulvin C. Itraconazole D. Miconazole E. Nystatin Amphotericine B, a polyene, is the most effective tx for many life threating fungal infx. Nystatin, a polyene, is used topically or orally, but not absorbed.

41. A new medication is being developed for cryptococcal meningitis that inhibits fungal colony growth by altering the fungal cell membrane composition. In human volunteers, this drug inhibits liver cytochrome P450-dependent metabolism of several drugs. Which of the following drugs fits this description? • Ketoconazole • Griseofulvin • Clotrimazole • Fluconazole • Clotrimazole

42. A 67 year old white male presents to your office with what he believes is a Candida infection. After proper workup, a candida infection is indeed confirmed. The patient claims that he read about flucytosine on the world wide web, and wants you to prescribe it for him. Which of the following medications will you likely also prescribe for him? A) aspirin B) simvastatin C) prednisone D) amphotericin B E) albuterol

43. You are about to put a pt on caspofungin for invasive Aspergilosis and your patient asks…..how does this drug work? • by inhibiting transpeptidase to block the cell wall synthesis • by inhibiting β-glucan to block the cell wall synthesis • by inhibiting ergosterol to block the cell wall synthesis • by inhibiting the LPS to block the cell wall synthesis

44. A 32 yr old male comes into the office complaining of ring like lesions on his arms and back. You suspect a fungal infection and run a KOH scraping to look at the lesions under the microscope. You observe mold hyphae that are not dimorphic. What of the following oral agents inhibits microtubule formation and can be used to treat dermatophytic infections? • Amphotericin B • Griseofulvin • Ketoconazole • Miconazole • Nystatin • B. Griseofulvin, which localizes in the keratinized tissues, inhibits the growth of dermatophytes by inhibiting microtubule assembly.