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Miscellaneous > Antifungals lecture > Flashcards

Antifungals lecture Flashcards

1
Q

Examples of molds

A

Aspergillus spp. (flavus, niger)

Rhizopus (Mucor)

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2
Q

Examples of yeasts

A 
Candida spp (albicans, glabrata, lusitaniae, krusei)
Cryptococcus
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3
Q

Examples of fungi

A

Blastomyces
Paracoccidiodomycoses
Coccidiodomycoses
Histoplasma

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4
Q

Benefits of fungi

-4 major

A

Medications: PCN & other B-lactam ABx (want to beat out the bacteria for energy); “statins”, for cholesterol

Food: mushrooms

Insect control: competitive exclusion to actively compete for nutrients

Biotechnology: yeast species used to produce peptide drugs

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5
Q

Types of fungal infections

A
  • Invasive apergillosis (immunosuppressed pts; “halo” sign)
  • Esophageal candidiasis (immunosuppressed pts; shiny white patches)
  • Invasive candidiasis: liver, spleen, lungs, brain, skin, etc
  • VVC
  • Candidemia (in the bloodstream)
  • Candiduria (urine)
  • Cryptococcosis (invasive to brain)
  • Blastomycosis
  • Histoplasmosis
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6
Q

Diagnosting fungal infections

  • Symptoms
  • Risk factors
  • Diagnostics
A

Symptoms: inflammatory response (leukocytosis, topical redness, etc.); fever (unknown origin; unresponseive to ABx)

Significant risk factors: immunocompromised, hospitalized, etc.

Diagnostics: tissue/ blood culture (i.e. bronchoscopy w/ tissue bx for lung infection)

  • Radiography (CT)
  • Serologic testing: for antibodies against some fungi (i.e. Coccidiomycosis)
  • Galactomannan assay (Aspergillus)
  • B-Glucan (Candida)
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7
Q

Levels of Fungal Infection Treatment

3 levels

A

Prophylaxis: preventative tx of a specific pathogen in an at-risk pt

Empiric: tx of a possible/probable fungal infection; based on presence of symptoms consistent w/ an infection; NO POSITIVE CULTURE DATA

Targeted: DEFINITIVE positive culture data, allows for targeted tx

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8
Q

Risk for Fungal Infections

A

IMMUNOSUPPRESSED PTS!

  • Invasive surgery (metabolic stress)
  • Chemotherapy (myelosuppression = decreased hematopoeisis)
  • Solid organ/ stem cell transplant recipient (immunosuppressive therapy, graft vs. host dz)
  • Certain dz (e.g HIV)
  • Alterations in normal flora d/t use of broad spectrum ABx (loss of competition)
  • Use of ICS (oral thrush)
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9
Q

Challenges of Fungal Dz

A
  • Difficult to diagnose
  • Potential toxicity of antifungals
  • Need for targeted therapy
  • Development of resistance to available agents (e.g. fluconazole)
  • Limited formulations (PO vs. IV vs. topical) for some agents
  • Aggressiveness of pathogen (can change to unstable w/in 24-48 hrs)
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10
Q

Six major classes of antifungals

A
  • Azoles (a)
  • Polyenes (b)
  • Flucytosine (c)
  • Echinocandins (d)
  • Griseofulvin
  • Terbinafine
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11
Q

Fungistatic vs. Fungicidal

A

Fungistatic drugs (MOST) inhibit growth; immune system can then complete eradication of fungi

Fungicidal drugs kill fungal pathogens; depends on mechanism of drug & ability to reach adequate [ ] at the site of action; PREFERRED (but not necessary) for treating immunocompromised pts

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12
Q

Amphoterecin

  • Class
  • MOA
  • Route
  • Considerations
A
  • Polyene
  • Binds to/disrupts ergosterol in fungal cell membrane –> pores –> leakage –> fungal cell death
  • ONLY AVAILABLE IN IV FORMULATION (can be made into oral or bladder rinse)
  • VERY LONG HALF-LIFE (15 days): remains in tissues for weeks after d/c of tx
  • NO DOSE ADJUSTMENT for renal/hepatic impairment
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13
Q

Spectrum of Activity: Amphoterecin

-Possible resistant organisms

A
  • BROAD-SPECTRUM:
  • Yeasts: CANDIDA ALBICANS
  • Cryptococcus
  • Histoplasma
  • Blastomyces
  • Coccidioides
  • Aspergillus
  • Mucor

Candida lusitaniae/ krusei; Pseudallescheria are resistant

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14
Q

INFUSION-RELATED EFFECTS of Amphoterecin

presentation, premedication, prevention

A

-Seen w/in min-hrs of infusion
Fever, chills, rigors, hypotension

-Premedicate with: ACETAMINOPHEN, DIPHENHYDRAMINE, Meperidene (prevents/ reduces rigors: shaking chills), Hydrocortisone (however, further immunosuppressive

  • Slowing infusion (over 2-4 hrs) may increase tolerability but still giving the whole dose
  • 1 mg test dose may be used to assess risk of anaphylaxis/ tolerability (then monitor 15-30 min): not a perfect predictor
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15
Q

CHRONIC EFFECTS of Amphoterecin

2 major

A

Renal toxicity: accumulates in the kidneys causing damage

  • Monitor SCr daily (may increase after 4-7 doses)
  • Azotemia (increased BUN, nitrogren compounds)
  • Renal tubular acidosis (hyperchloremia, decreased H+ excretion)
  • Potassium & magnesium wasting
  • PRE-HYDRATE WITH SALINE-BASED SOLN: helps decrease/ slow nephrotoxicity (C/I for CHF or any fluid-intolerant pts)

Hepatic toxicity: increased LFTS (ALT, etc)

*Don’t need dose adjustments for these patients but Ampho WOULD NOT be 1st line choice

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16
Q

Lipid Formulations of Amphoterecin

  • Use
  • Three major products
  • Limitations
A

-Created to improve tolerabilty; amphoterecin is packaged in hydrophilic portions of lipid molecules to help deliver the drug to affected tissues

  • Abelcet (lipid complex; “ribbons”)
  • Amphotec (colloidal dispersion; “globules”)
  • Ambisome (liposomal) - least toxic
  • High expense limits use (only when needed)
  • Reduces toxicity, doesn’t eliminate it
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17
Q

Major Uses for Amphoterecin

  • Limitations
  • Administration
A
  • Reserved for LIFE-THREATENING OR REFRACTORY INFECTIONS (not 1st line); Candida, Aspergillus, mucor, etc.
  • Toxicity; better tolerated agents limit use!
  • Given as IV infusion over 2-6 hrs; dose range 0.5-2 mg/kg/day (vs. lipid which is higher)
  • Dosed to reach cumulative 1-2 g (for regular ampho)
  • Can be made into bladder irrigation, topical gtts, intravitreal (eye) injections
18
Q

Flucytosine-Related to 5-FU (a common chemotherapeutic)

  • MOA
  • Limitations
  • Benefits
A

-Taken up by fungal cells, converted; inhibit fungal DNA/ RNA synthesis; SYNERGISTIC ACTION WITH AMPHOTERECIN

  • Used less d/t other, better choices
  • Only available in PO tablets
  • Large volume of distribution (CNS infections! i.e. Cryptococcal meningitis)
  • Can be used with amphoterecin for combination tx of Cryptococcus & Candida meningitis
19
Q

ADVERSE EFFECTS of Flucytosine

A
  • Related to metabolism of 5-FU by bacteria in GI tract
  • Myelosuppression is dose-limiting! e.g. anemia, thrombocytopenia, leukopenia
  • Hepatotoxicity (increased LFTs)
20
Q

CLINICAL USE of Flucytosine

A
  • Mostly to treat cryptococcal meningitis
  • ALMOST ALWAYS USED IN COMBINATION with other antifungal (ampho): d/t rapid development of resistance
  • sometimes combined with an azole (e.g. itraconazole)
21
Q

Azole Antifungals

-Two classes, examples

A

Imidazoles (contain a carbon in the ring)

  • Ketoconazole
  • Miconazole
  • Clotrimazole

Triazoles (contain a nitrogen in the ring)

  • Itraconazole
  • Fluconazole
  • Voriconazole
  • Posaconazole
22
Q

Azoles

  • MOA
  • Adverse effects
A

-Inhibit FUNGAL cytochrome P450-dependent enzyme (also inhibits human CYP450) –> reduces formation of ergosterol; considered FUNGISTATIC

  • G.I upset
  • Increased LFTs (not as closely monitored; indicated if symptomatic) – non-infectious hepatitis
  • Drug Interactions!
23
Q

Drug Interactions (Azoles)

  • Major target
  • Enzyme selectivity
  • Examples of drugs & effect
A
  • INHIBITOR of CYP450 enzymes, esp 3A4
  • Selectivity of imidazole < triazole = imidazoles have more effect on human CYP450 = more drug interactions/ side effects

-Inhibitor = decreased metabolism = increased [drug]
-Examples:
Warfarin: anticoagulant; RISK FOR BLEEDING; monitor INRs
Phenytoin (anti-seizure meds thatn can cause seizures in [high])
Tacrolimus; Cyclosporine; Ca+ Channel blockers; etc.

24
Q

Ketoconazole

  • Enzyme selectivity
  • Limitations
  • Use
A
  • LESS selective for FUNGAL CYP450 enzymes = more likely to affect human enzymes
  • Less potent than newer azoles; reduced role for treating systemic infections
  • TOPICAL FUNGAL INFECTIONS: e.g. Nizoral shampoo/cream
25
Q

Itraconazole

  • Route
  • Considerations
  • Spectrum of activity
  • Uses/ limitations
A
  • Available in PO capsules, suspension, IV formuation; IV & PO suspension made w/ cyclodextrin –> LIMITED USE IN RENAL INSUFFICIENCY D/T RISK FOR NEPHROTOXICITY
  • Should be taken with food to increase absorption (acidic enviro); AVOID taking with acid reducers (H2 antags, PPIs)
  • Covers Candida spp & Aspergillus (spp): replaced by voriconazole d/t better bioavailability & penetration of CNS
  • In Onychomycosis: high recurrence rate; not covered by insurance
  • Histplasmosis, Blastomycosis
26
Q

Fluconazole (Diflucan)

  • Route
  • Dose
  • Considerations
  • Uses/ limitations
A
  • Available in PO tablets, sol’n & IV formulation
  • Dosed according to indication/ severity: e.g. VVC vs. CNS/ candidemia
  • Very well-tolerated, good volume of distribution (incl CSF)
  • DOSE ADJUST in renal insufficiency (CrCl <50 ml)
  • TREATMENT AND PROPHYLAXIS of coccidiodal & cryptococcal meningitis
  • TREATMENT of Candidemia, candiduria, esophageal candidiasis, VVC, other systemic candidiasis
  • PROPHYLACTIC for neutropenic pts (i.e. chemo pts)

NO ACTIVITY AGAINST ASPERGILLUS
-resistance seen in C. krusei/ glabrata

27
Q

Voriconazole

  • Route
  • Dose
  • Considerations
  • Adverse effects
  • Spectrum of Activity/ Use
A
  • PO tablets, sol’n, IV formulations
  • Loading dose for 1 day to get to therapetuic [ ] faster; then maintenance dose (typically, PO is ~200 mg b.i.d)
  • EXCELLENT PO bioavailability; requires dose adjustment in HEPATIC IMPAIRMENT (not renal)
  • ADEs incl: hepatic toxicity, rash (uncommon), visual changes (mostly involving color; goes away)
  • CANDIDA SPP (INCL FLUCONZAOLE-RESISTANT spp)
  • ASPERGILLUS SPP.
  • Rare spp seen in HIV, leukemia (Scedosporium, Fusarium)

-TREATMENT OR PROPHYLAXIS OF INVASIVE FUNGAL INFECTIONS (esp in oncology)

28
Q

Posaconazole

  • Route
  • Dose
  • Considerations
  • Spectrum of activity
  • Use
A
  • PO sol’n, tablets, IV
  • Doses differ by formulation, indication:
    e. g. higher dose for prophylaxis vs. oral thrush: SUSPENSION ONLY, lower dose x 13 days; REFRACTORY oral thrush: suspension only, higher dose

-Increased bioavailabilty after a FULL meal or with an acidic carbonated drink

  • BROAD SPECTRUM AGAINST: CANDIDA SPP, ASPERGILLUS SPP, other molds
  • PROPHYLAXIS of fungal infxn for immunosuppressed pts: acute leukemia, stem cell transplant
  • SALVAGE THERAPY in systemic fungal infections
29
Q

Topical Azoles

  • Examples
  • Spectrum of activity
  • Formulations, potency
  • Uses
A
  • Oxiconazole, butoconazole, clotrimazole, miconazole, econazole, etc.
  • Similar activity against common dermatophytoses
  • Available in OTC preparations that vary in potency (affects duration of tx); commonly used as creams, powders
  • VVC
  • Athlete’s foot
  • Diaper rash
  • Other topical yeast infections
30
Q

Echinocandins: newest class

  • Examples
  • Spectrum of activity
  • Route
  • MOA
A

-Caspofungin, micafungin, anidulafungin

  • ACTIVE AGAINST CANDIDA (fungicidal) & ASPERGILLUS (fungistatic)
  • May be combined with another drug to completely cover Aspergillus (ID specialist)
  • IV FORMULATION ONLY (destroyed by stomach acid; must be through IV line, not a push)
  • Inhibits B-1,3 glucan synthase; inhibits creation of fungal cell wall component; disrupts fungal cell integrity –> cell death
31
Q

ADVERSE EFFECTS of Echinocandins

  • Direct reactions
  • Drug interactions
A
  • Typically, well-tolerated
  • G.I effects; flushing reactions if infused too fast (follow guidelines)
  • Increased LFTs (esp for at-risk pts)
  • Reduced potential compared to azoles
  • Increases [drug] of: immunosuppressants, antihypertensives, etc.
32
Q

USE of Echinocandins

A
  • Limited by IV formulation
  • Often for REFRACTORY CASES (can’t tolerate or didn’t resp to azoles); pts with RENAL OR HEPATIC IMPAIRMENT
  • Caspofungin: disseminated dz, SALVAGE TX of ASPERGILLOSIS, empiric tx of possible fungal infection
  • Micafungin: esophageal candidiasis, candidemia, PROPHYLAXIS for CANDIDA in SCT pts
  • Anidulafungin: esophageal candidiasis, invasive candidiasis
33
Q

Griseofulvin

  • MOA
  • Considerations
  • Use
A

-Binds to keratin in skin & prevents spread of fungal
infection

-POOR PO absorption; INCREASED with high-fat meal
Takes weeks for effects to be seen as skin cells turnover
RISK OF LIVER TOXICITY (monitor LFTs qmonthly)

-Sometimes used for treatment of fungal skin & nail infections (dermatophytoses)

34
Q

Terbinafine

  • MOA
  • Route/ dose
  • Considerations
  • Use
A
  • Interferes with ergosterol synthesis –> leads to fungicidal buildup of squalene epoxidase
  • Available as topical cream or PO tablets: dosed over several months
  • RISK OF HEPATIC TOXICITY WITH PO TABLETS: monitor LFTs
  • Used for dermatophytoses, ESP ONYCHOMYCOSIS
35
Q

Tolnaftate

  • Action
  • ADEs
  • Use
A
  • Similar action to terbinafine (lower potency)
  • Risk of skin irritation in sensitive individuals
  • NO ACTIVITY AGAINST CANDIDA SPP INFECTIONS!!

-Commonly used in TOPICAL CREAMS, SPRAYS
Treatment of ATHLETE’S FOOT (tinea pedis) and other superficial fungal infections ; usually INEFFECTIVE for onychomycosis

36
Q

Nystatin

  • Class
  • Route
  • Use
A
  • Polyene macrolide antifungal (same as amphoterecin)
  • Powder, cream, vaginal suppository, PO suspension

-Active against MOST CANDIDA SPP!!
Oral thrush – PO suspension – “swish & spit”
VVC – cream or suppository – azoles are more common
Candidal skin infections – cream or powder

Generally well-tolerated topically

37
Q

Selecting an Antifungal

-4 major steps

A
  • Identify pt at risk for or with a fungal infection (immunosuppressed, chemo, neutropenic, etc)
  • Consider level of tx: prophylaxis vs. empiric (broad) vs. targeted (narrow)
  • Consider possible fungi involved/ severity of infection
  • Select Rx from available agents based on: route, spectrum of activity, availability, cost, tolerability
38
Q

28 y.o M construction worker who wears boots all day w/ chronic tinea pedis c/o intense ITCHING between toes, skin appears WHITE, MACERATED, CRACKED
Dx: athlete’s foot fungus

How would you treat?
What non-pharmaceutical advice would you give this pt?

A

-No need to consider potent antifungals like amphoterecin, azoles, echinocandins

-Topical antifungal:
-Creams are more potent than powders (greater absorption)
Options: Lotrimin (clotrimazole) or Lamisil (terbinafine)
-Counsel pt with directions
-Non-pharmaceutical tx: keep feet dry, change socks frequently, avoi walking around with bare feet, esp near water

39
Q

21 y.o M admitted following car accident; underwent SURGERY to repair internal injuries to abd; currently admitted to the ICU; receiving TPN (total parenteral nutrition); SPIKED FEVER 3 DAYS AGO, BLOOD CX = ( - )
has been receiving BROAD-SPECTRUM ABX

  • What is the most likely cause of his fever?
  • How would you treat?
A
  • Pt is at risk for systemic fungal infection like Candidemia
  • Want to select an agent that covers Candida but minimize potential for ADEs
  • Options: fluconazole, voriconazole, echinocandins, ampho
  • Fluconazole: best-tolerated, lost cost
  • Others would not be wrong, but may be more expensive (vori) or more toxic (ampho)
  • MONITOR DRUG INTERACTIONS
40
Q

44 y.o W with leukemia, severely NEUTROPENIC; Chest CT shows presence of HALO SIGN. Fungal infection is suspected but no definitive proof

  • What are you suspected d/t CT findings? How would you confirm?
  • How would you treat in the meantime?
A

-Invasive aspergillosis; would need tissue bx

  • Empiric antifungal tx needed!! Should cover Aspergillus, Candida (& other)
  • Options: Vori, itraconazole, posaconazole, amphoterecin (+ lipid form), echinocandins
  • Ampho: most toxic
  • Lipid amphos are expensive
  • Posa: only approved for prophylaxis, OPC
  • Echinocandins: NOT COMMON as 1st line
  • Vori: better bioavailability & broader spectrum than itroconazole!! (multiple options, vori seems best)

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