Antifungal Medications Flashcards

Question

Clinical Use of Amphotericin

Answer 1

ï Toxicity and better tolerated agents limit use ï Reserved for life-threatening or refractory infections ñ Candida, Aspergillus, mucor, etc ï Given as intravenous infusion over 2-6 hours ï Dose range 0.5-1 mg/kg/day ï Lipid ampho doses 3-5 mg/kg/d ï Dosed to reach cumulative 1-2 grams (only for regular ampho, not lipid forms) ï Can be made into bladder irrigation, topical ointments

Answer 2

ï Created in 1950 while searching for anticancer agents ï Used less now due to other better choices ï Related to fluorouracil (5-FU) ï Only available in oral tablets ï Large volume of distribution -CNS

Answer 3

ï Taken up by fungal cells and converted to 5-FU and then 5-FdUMP and 5-FdUTP ï These molecules inhibit fungal DNA and RNA synthesis ï Synergistic action with amphotericin

Answer 4

``` ï Related to metabolism to 5-FU by bacteria in GI tract ï Myelosuppression is dose limiting ñ Anemia ñ Thrombocytopenia ñ Leukopenia ï Hepatotoxicity ( LFTs) ```

Answer 5

ï Mostly used to treat cryptococcal meningitis ï Almost always used in combination with another antifungal ñ Rapid development of resistance ñ Usually combined with amphotericin ñ Sometimes combined with an azole (eg, itraconazole)

Answer 6

named for the 5 membered azole ring Imidazoles Ketoconazole Miconazole Clotrimazole ``` Triazoles Itraconazole Fluconazole Voriconazole Posaconazole ```

Answer 7

Inhibit fungal cytochrome P450-dependent enzyme lanosterol 14-·-demethylase Reduces formation of ergosterol Considered fungistatic (not fungicidal)

Answer 8

GI upset LFTs Non-infectious hepatitis

Answer 9

ï Azoles also inhibit human CYP450 enzymes ñ CYP450 3A4 is major target ñ Results in many significant drug interactions due to enzyme inhibition ñ Enzyme selectivity of imidazole < triazoles ï Means imidazoles have more effect on human CYP450 enzymes ï More significant drug interactions and side effects with imidazoles (but interactions with triazoles are still relevant)

Answer 10

``` ï Leads to ↓metabolism of other drugs metabolized by affected CYP450 enzymes ñ Example: ï Warfarin ï Tacrolimus ï Cyclosporine ï Phenytoin ï Calcium channel blockers ```

Answer 11

ï Less selective for fungal CYP450 enzymes ï Not as potent as newer azoles ñ Reduced role for treating systemic fungal infections ï Used for topical fungal infections ñ NizoralÆ shampoo ñ NizoralÆ cream

Answer 12

ï Available in oral capsules and suspension, and IV formulation ï Dosed 100-400 mg/day ï Should be taken with food to increase absorption ï Reduced bioavailability when capsules taken with acid reducers (H2 antags, PPIs) ï IV and oral suspension made with cyclodextrin which limits use in renal insufficiency

Answer 13

ï Available in oral tablets, solution, and IV formulation ï Dosed 100-800 mg/day ñ Dose varies for indication and severity ï Very well tolerated ï Good volume of distribution including CSF ï Dose adjust in renal insufficiency

Answer 14

ï Used for tx and prophylaxis of coccidiodal and cryptococcal meningitis ï Effective in treatment of candidemia, candiduria, esophageal candidiasis, VVC, and other forms of systemic candidiasis ï Used for prophylaxis in neutropenic patients ! NO activity against Aspergillus ! Resistance seen in C.krusei and C.glabrata

Answer 15

ï Oral tablets, solution, and IV formulations ï Loading dose 4 mg/kg q12h x2 ï Maintenance dose 2 mg/kg bid ñ Typical oral dose 200 mg bid ï Excellent oral bioavailability ï Adverseeffectsincludehepatictoxicity,rash, visual changes ï Requires dose adjustment in hepatic impairment but not renal insufficiency

Answer 16

``` ï Broad spectrum of activity ñ Candida sp. ï Including fluconazole resistant Candida sp. ñ Aspergillus sp. ñ Scedosporium apiospermum ñ Fusarium ï Used for treatment or prophylaxis of invasive fungal infections ```

Answer 17

``` ï Broad spectrum of action against ñ Candida sp. ñ Aspergillus sp. ñ Other molds ï Approved for use as prophylaxis of fungal infections in immunosuppressed patients ñ Acute leukemia and SCT ï May be used for salvage therapy in systemic fungal infections ```

Answer 18

ï Available in oral solution, IV, and tablets ï Doses differ by formulation and indication: ï For prophylaxis: ñ IVandtablets:LD300mgIVbidx2onday1,then300mgIV daily ñ Susp: 200 mg PO tid ï For oropharyngeal candidiasis (suspension only) ñ LD 100 mg PO bid on day1, then 100 mg daily x13dfor OPC ï For refractory OPC (suspension only) ñ 400 mg PO bid  Increase bioavailability when taken after a full meal or with an acidic carbonated beverage

Answer 19

ï Oxiconazole, butoconazole, clotrimazole, miconazole, econazole, plus more ï Available in many over the counter preparations ï Similar activity against common dermatophytoses ï Vary in potency which affects durations of treatment ï Commonly used in topical products such as cream or powder for ñ Vulvovaginal candidiasis (ie, vaginal yeast infections) ñ Athleteís foot (ie, tinea pedis) ñ Diaper rash ñ Other topical yeast infections

Answer 20

``` ï Newest class of antifungals ï Three agents available in U.S. ñ Caspofungin (CancidasÆ) ñ Micafungin (MycamineÆ) ñ Anidulafungin (EraxisÆ) ï Active against Candida and Aspergillus ï Only available IV ```

Answer 21

ï Inhibit ‚-1,3-glucan synthase ï Inhibits creation of component of fungal cell walls ï Disrupts fungal cell integrity and leads to cell death ï Fungicidal against Candida ï Fungistatic against Aspergillus

Answer 22

``` ï Typically, very well tolerated ï GI effects ï Flushing reactions if infused too fast ñ Follow manufacturersí recommendations ï  LFTs ```

Answer 23

``` ï Greatly reduced compared to azoles ï Caspofungin ñ Cyclosporine and tacrolimus (immunosuppressives) ï Micafungin ñ Sirolimus (immunosuppressive), nifedipine (antihypertensive), cyclosporine ï Anidulafungin ñ Tacrolimus ```

Answer 24

ï Limited by IV formulation (no oral) ï Often used in refractory cases or in patients with renal or hepatic impairment ï Caspofungin ñ Disseminated candidiasis, salvage treatment of aspergillosis, or empiric treatment of possible fungal infection ï Micafungin ñ Esophageal candidiasis, candidemia, and prophylaxis of Candida infections in SCT patients ï Anidulafungin ñ Esophageal candidiasis and invasive candidiasis

Answer 25

ï Sometimes used for treatment of fungal skin and nail infections (dermatophytoses) ï Very poor oral absorption is increased with a high fat meal ï Acts by binding to keratin in skin and preventing spread of fungal infection ï Takes weeks for effects to be seen as skin cells turnover ï Risk of liver toxicity

Answer 26

ï Used for treatment of dermatophytoses, especially onychomycosis ï Interferes with ergosterol synthesis by inhibiting squalene epoxidase ñ Leads to fungicidal buildup of squalene and low production of ergosterol ï Dosed over several months ï Availableastopicalcreamortablets ï Risk of hepatic toxicity with oral tablets ñ Need to monitor LFTs

Answer 27

ï Commonly used in topical creams and sprays ñ Treatment of athleteís foot (tinea pedis) and other superficial fungal infections (TinactinÆ products) ñ No activity against infections involving Candida species ñ Usually ineffective for onychomycosis ï Similar action to terbinafine but lower potency ï Risk of skin irritation in sensitive individuals

Answer 28

ï Polyene macrolide antifungal ï Available in powder, cream, vaginal suppositories, and oral suspension ï Active against most Candida sp. ñ Oral candidiasis (thrush) (oral suspension) ñ Vaginal candidiasis (cream or vaginal suppository) ñ Candidal skin infections (cream or powder) ï Very well tolerated topically

Answer 29

ï Identify patient with, or at risk for, a fungal infection ï Consider level of treatment (prophylaxis vs empiric/targeted treatment) ï Consider the possible fungi involved and severity of infection ï Select therapy from available agents based on route, spectrum of activity, availability, cost, tolerability