Antifungal Medications Flashcards
4 Types of Mold
Aspergillus, mucor
Aspergillus flavus = MC
Aspergillus niger
Rhizopus
4 Types of Fungi
Blastomyces
Paracoccidiodomycoses
Coccidiodomycoses
Histoplasma
5 Types of Yeast
Candida sp. Candidaalbicans Candidaglabrata Candidalusitania Candidakrusei
Benefits of Fungi
Source for many medications
Penicillin and other beta-lactam antibiotics
HMG-CoA reductase inhibitors (ìstatinsî)
Food
Edible mushrooms
Insect control
Process of competitive exclusion to actively compete
for nutrients
Biotechnology
Yeast species used as machinery to produce peptide
drugs (ex. Erwinia asparaginase)
Types of Fungal Infections
Invasive aspergillosis Esophageal candidiasis Invasive candidiasis Vulvovaginal candidiasis Candidemia Candiduria Cryptococcosis Blastomycosis Histoplasmosis
Candida causes invasive infections where?
Body tissues (ex. liver, spleen, lungs, brain )
Blood (ex, candidemia)
Genitourinary tract (ex. vulvovaginal candiasis)
Diagnosis of Fungal Infections
Symptoms
Inflammatory response (↑WBC, topical redness, etc)
Fever
Risk factors Tissue/blood culture Radiography Serological testing For antibodies against some fungi (eg, Coccidiomycosis) Galactomannan assay (Aspergillus) Glucan (Candida)
Levels of Fungal Infection Treatment
Prophylaxis
Empiric
Targeted
Prophylaxis
Preventive treatment of a specific pathogen in an at risk patient
Empiric
Treatment of a possible or probable fungal infection
Based on presence of symptoms consistent with a fungal infection but no positive culture
Targeted
Definitive positive culture data exists allowing for targeted treatment
Risk of Fungal Infections
Increased in immunosuppressed patients
Metabolic stress from invasive surgery
Myelosuppression from chemotherapy
Immunosuppression after solid organ or stem cell
transplant
Immunosuppressive diseases (eg, HIV)
Alterations in normal flora due to use of broad
Challenges of Fungal Infections
Difficult to diagnose
Potential toxicity of available agents
Need for targeted therapy
Development of resistance to available agents
Limited formulations (oral vs IV vs topical) for
some agents
Aggressiveness of pathogen
Classes of Antifungals
Azoles Polyenes Flucytosine Echinocandins Terbinafine Griseofulvin
4 Types of Azoles
Fluconazole
Itraconazole
Voriconazole
Posaconazole
2 Types of Polyenes
Nystatin
Amphotericins
3 Types of Echinocandins
Caspofungin
Micafungin
Anidulafungin
Fungistatic vs. Fungicidal
Fungistatic drugs inhibit growth
Immune system can then complete eradication of
pathogenic fungi
Fungicidal drugs kill fungal pathogens
Dependent on mechanism of drug and ability to
reach adequate concentration at the site of action
Preferred (but not necessary) for treatment in
immunocompromised patients
Amphotericin
Polyene macrolide antifungal **Only available in an IV formulation Can be made into an oral mouth rinse Very long half-life (15 days) Remains in the body tissues for weeks after course of therapy is discontinued No dose adjustment in renal or hepatic impairment Toxicity may limit use or alter schedule of dosing
Mechanism of Amphotericin
Binds to and disrupts ergosterol in fungal cell membrane Disrupts membraneís integrity leading to creation of pores in cell membrane Alters permeability of membrane Leads to leakage of intracellular components out of the cell Fungal cell death ensues
Activity of Amphotericin
Broad spectrum Yeast Candidaalbicans Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Aspergillus Mucor (Rhizopus)
Resistant Organisms
Candidalusitaniae
Pseudallescheriaboydii
Candidakrusei(sometimes)
Adverse Effects of Amphotericin
Infusion related reactions
Fever, chills, rigors, hypotension
Premedicate with:
Acetaminophen
Diphenhydramine
Meperidine
Hydrocortisone
Slowing infusion may increase tolerability
1 mg test dose may be used to assess risk of
anaphylaxis/tolerability
Give test dose then monitor for 15-30 minutes
Chronic Adverse Effects of Amphotericin
Renal toxicity Scr Azotemia (↑ in nitrogen compounds like BUN) Renal tubular acidosis (hyperchloremia) Potassium and magnesium wasting Prehydrate with saline-based hydration Hepatic toxicity LFTs
Lipid Formulations Amphotericin
Created to improve tolerability
Three commercially available products
AbelcetÆ (amphotericin B lipid complex- ABLC)
AmphotecÆ (amphotericin B colloidal dispersion- ABCD)
AmbisomeÆ (liposomal amphotericin)
All package amphotericin in the hydrophilic portions
of lipid molecules
Help deliver amphotericinto affected tissues
Reduce toxicity,but dont eliminate it
High expense limits use
Clinical Use of Amphotericin
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
Flucytosine
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
Mechanism of Flucytosine
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
Adverse Effects of Flucytosine
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)
Clinical Use of Flucytosine
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)
Azole Antifungals
named for the 5 membered azole ring
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Triazoles Itraconazole Fluconazole Voriconazole Posaconazole 
Mechanisms of Action of Azoles
Inhibit fungal cytochrome P450-dependent
enzyme lanosterol 14-·-demethylase
Reduces formation of ergosterol
Considered fungistatic (not fungicidal)
Adverse Effects of Azoles
GI upset
LFTs
Non-infectious hepatitis
Azole Drug Interactions
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)
Drug Interactions of Azoles
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
Ketoconazole
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
Itraconazole
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
Fluconazole
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
Fluconazole used to treat…
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
Voriconazole
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
Voriconazole used to treat…
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
Posaconazole
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
Posaconazole used for..
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
Topical Azole Antifungals
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
Echinocandins
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
Mechanism of Echinocandins
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
Adverse Effects of Echinocandins
ï Typically, very well tolerated ï GI effects ï Flushing reactions if infused too fast ñ Follow manufacturersí recommendations ï LFTs
Echinocandins potential for Drug Interactions
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
Use of Echinocandins
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
Griseofulvin
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
Terbinafine
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
Tolnaftate
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
Nystatin
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
Selecting Antifungal Treatment
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
