Improving Clinical Outcomes in Fungal

Infection Control and Management

DISCLAIMER The information within this CME/CE activity is for continuing education purposes only, and is not intended to substitute for the medical judgment of the healthcare provider. Recommendations for use of any particular therapeutic agents or methods are based upon the best available scientific evidence and clinical guidelines. Reference in this activity to any specific commercial products, process, service, manufacturer, or company does not constitute its endorsement or recommendation.

PICTURE Name TITLE Organization

Faculty Biography

Vanthida Huang, PharmD, BSPHM, FCCP

Associate Professor

Mercer University College of Pharmacy

DISCLOSURES I do not intend to discuss an off-label use of a product during this activity.

I have not had any relevant financial relations during the past 12 months to disclose OR I currently have or have had the following relevant financial relations to disclose:

If you have relevant relations to disclose, please list

Commercial Interest

Relationship with Commercial Interest

Type of Compensation Received

OBJECTIVES

1. Identify populations at risk for invasive fungal infections based on

epidemiology and clinical presentation

2. List clinical pharmacology, pharmacokinetics, and mechanisms of

action for currently available antifungals used in treating invasive

fungal infections.

3. Discuss current Infectious Diseases Society of America guidelines for

the treatment of invasive fungal infections.

FUNGI KINGDOM

4/3/2014 6

Opportunistic fungi

Normal flora

Candida spp.

Ubiquitious in our environment

Aspergillus spp.

Cryptococcus spp.

Mucor spp.

Newly emerging fungi

- Fusarium

- Scedosporium

Endemic geographically restricted

- Blastomyces spp.

- Coccidiodes spp.

- Histoplasma spp.

4/3/2014 7

FUNGI KINGDOM

Solid organ transplant

− 5-42%

Bone marrow transplant

− 15-25%

Intensive care unit (ICU)

− 17%

Incidence of Invasive Fungal Infections

4/3/2014 8

Singh N. Clin Infect Dis 2000;31:545-553. Vincent JL. Intens Care Med 1998;24:206-216.

ANTIFUNGAL AGENTS Polyenes

Echinocandins

Triazoles

Antimetabolitesrimidine Analogue

4/3/2014 9

Eukaryotes with defined nucleus within nuclear membrane

Rigid walls

– Glucans

– Chitin

– Cellulose

Cytoplasmic membrane (site of antifungal action)

– Sterol

– Glycoproteins

– Lipids

FUNGAL CHARACTERISTICS

4/3/2014 10

ANTIFUNGAL TARGETS: Many to Choose from

4/3/2014 11

DNA DNA Polymerase Cell Membrane Cell wall

Squalene Epoxidase

SE Cytochrome P450

P450

Ergosterol Squalene Lanosterol

-1,3-glucan

-1,3-glucan Synthase

ANTIFUNAL ACTIVITY

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P450 SE

Echinocandins Antimetabolites

Azoles

Allylamines Polyenes

Amphotericin B

Amphotericin B deoxycholate (AMBd; Fungizone®)

Amphotericin B Colloidal Dispersion (ABCD; Amphotec®)

Liposomal Amphotericin B (LAMB; AmBisome®)

Amphotericin B Lipid Complex (ABLC; Ablecet®)

Nystatin

POLYENES

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MOA: bind ergosterol in fungal cell membrane, leading to cell death

Considerable toxicity

− Nephrotoxicity

− Electrolyte wasting

− Infusion-related reactions

Pharmacokinetic

– Poorly absorbed

– Highly distributed (not detectable in CNS)

– Metabolism and elimination unknown

Pharmacodynamic

− Concentration-dependent

POLYENES

4/3/2014 14

Broad antifungal spectrum

− Candida spp. (except C. lusitaniae)

− Cryptococcus neoformans

− Dimorphic fungi

− Aspergillus spp., Zygomycetes spp.

− Fusarium spp., Scedosporium spp.

Toxicity is considerable

Most clinical experience with amphotericin B deoxycholate

AMPHOTERICIN B

4/3/2014 15

AMPHOTERICIN B NEPHROTOXICITY

4/3/2014 16 http://www.doctorfungus.org/thedrugs/Nephrotoxicity.php

Nephrotoxicity (SCr ≥ 2.5 mg/dL raised risk of

− Hemodialysis

− Death

Risk particularly high in bone marrow transplantation (BMT) or acute leukemia patients

AMPHOTERICIN B SIGNIFICANCE NEPHROTOXICITY

4/3/2014 17 Wingard JR et al. Clin Infect Dis 1999;29:1402-1407.

− Formulations

− Amphotericin B Colloidal Dispersion (ABCD; Amphotec®)

− Liposomal Amphotericin B (LAMB; AmBisome®)

− Amphotericin B Lipid Complex (ABLC; Abelcet®)

Efficacy differences: lipid formulation ≥ AMBd

Safety Profiles

− Nephrotoxicity: AMBd >> ABCD ≥ ABLC > LAMB

− Infusion reactions: AMBd >> BCD > ABLC > LAMB

Product cost (AWP)

− AMBd < ABCD < ABLC < LAMB

AMPHOTERICIN B LIPID FORMULATIONS

4/3/2014 18 Wingard JR et al. Clin Infect Dis 1999;29:1402-1407.

TRIAZOLES → “Azoles”

4/3/2014 19

Fluconazole (Diflucan)

Itraconazole (Sporanox)

Voriconazole (Vfend)

Posaconazole (Noxafil)

Inhibit fungal cytochrome P450 (14-demethylase), decreasing ergosterol formation

Variable antifungal spectrum

− Fluconazole ineffective against some C. glabrata, C. krusei, Aspergillus spp., molds

− Itraconazole is effective against Aspergillus

− New agents have extended spectrums

Drugs of choice for many fungal infections

Concerns

− Drug interactions

− Fluconazole resistance

− Prophylaxis

TRIAZOLES → “Azoles”

4/3/2014 20

Adverse Events

− Hepatotoxicity

− Rash

Pharmacokinetic

− Absorption variable between agents

− Widely distributed

− All have some hepatic metabolism

− Fluconazole excreted renally

Pharmacodynamic

− Time-dependent

− Fungicidal vs. molds, fungistatic vs. yeasts

TRIAZOLES → “Azoles”

4/3/2014 21

Utility

– Treatment of many forms of candidiasis

– Prophylaxis of candidiasis

– Treatment of some dimorphic fungal infections

Available injectables, tablets, and suspension

Spectrum

– Yeasts including many Candida and Cryptococcus excepts C. krusei and C. glabrata (variable)

– Some dimorphic fungi

– NO activity against mold

Adverse effects

Drug interactions

FLUCONAZOLE

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Utility

– Dimorphic fungal infections

– Onychomycosis

Available in capsules and oral suspension

– Issues with formulations

Spectrum

– Yeasts including Candida and Cryptococcus

– Aspergillus, many dematiaceous moulds, and dimorphic fungi

Adverse Events

Drug interactions

ITRACONAZOLE

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Utility

– Invasive Aspergillosis and other mold infections

– Invasive candidiasis

– Esophageal candidiasis

– Febrile neutropenic?

Available injectables, tablets, and oral suspension

Spectrum

– Yeasts including Candida and Cryptococcus

– Molds including Aspergillus, Fusarium, Scedosporium, dematiaceious moulds, and endemic fungi

VORICONAZOLE

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Pharmacokinetic

– Well absorbed, hepatically metabolized

– Non-linear

– SBECD of IV form is renally eliminated

Adverse Events

– Visual effects

– Hepatotoxicity

– Visual hallucinations

Drug interactions

VORICONAZOLE

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Utility

– Approved for prophylaxis of fungal infections

– Mold infections

Pharmacokinetic

– Suspension requires high fat meal or acidic beverage

– PO tablet (delayed-release) and injectable form

Spectrum

– Yeasts including Candida and Cryptococcus

– Molds including Aspergillus and Zygomycetes

Drug interactions

Adverse Events

POSACONAZOLE

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4/3/2014 27

Sporanox® (itraconazole) capusles package insert. Janssen Pharmaceuticals, Inc. Vfend® (voriconazole) package insert. Pfizer, Inc.

Caspofungin (Cancidas®)

Micafungin (Mycamine®)

Anidulafungin (Eraxis®)

ECHINOCANDINS

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Target of Echinocandin Antifungals

4/3/2014 29

Rho1p

Fks1

p

Fks2

p

GTP binding site

UDP-glucose

Beta-1,3 glucan synthase complex

Yeast

Fungal Cell Wall

beta 1,3 glucans beta1,6 glucans

mannoproteins

Beta 1,3 glucan synthase

Chitin

Lipid bilayer with ergosterol

Beta 1,3 glucan chain

MOA: inhibit -1,3-glucan synthase, decreasing -1,3-glucan production

Antifungal spectrum

− Strong in vitro activity against clinical Candida spp.

Weaker against C. parapsilosis

− Active against Aspergillus spp.

− Ineffective for Cryptococcus, many molds

− Efficacy unknown for many mycoses

Intravenous (IV) only

Fungicidal vs. yeasts, pseudo-static vs. molds

ECHINOCANDINS

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Pharmacokinetic

− Poor bioavailability

− Well distributed

− Variable metabolism

− Not eliminated renally

Pharmacodynamic

− Concentration-dependent

Adverse Events

− Hepatotoxicity

− Infusion-related reactions

− Phlebitis

Expensive

ECHINOCANDINS

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ECHINOCANDINS

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Caspofungin (Cancidas®)

Micafungin (Mycamine®)

Anidulafungin (Eraxis®)

Invasive candidiasis Esophageal candidiasis Febrile neutropenia Salvage aspergillosis

Invasive candidiasis Esophageal candidiasis Prophylaxis in HSCT patients

Invasive candidiasis Esophageal candidiasis

Hepatic metabolism, not by P450

Hepatic metabolism, not by P450

Enzymatic degradation in plasma

Possibly added hepatotoxicity with cyclosporine

↑ AUCs of sirolimus, nifedipine

No known interactions

70 mg x1, then 50 mg q24h 35 mg in hepatic disease

50-150 mg/day, depending on indication

200 mg x 1, then 100 mg q24h

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DOSES

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Class Agent Loading Dose Maintenance Dose

Azole Fluconazole (Diflucan®)

12 mg/kg IV x 1 dose 6 mg/kg IV q24h

Azole Voriconazole (VFend®)

6 mg/kg IV q12h x 2 doses 3-4 mg/kg IV q12h

Azole Posaconazole (Noxafil®)

None 400 mg PO q 12h

Echinocandin Caspofungin (Cancidas®)

70 mg IV x 1 dose 50 mg IV q24h

Echinocandin Anindulafungin (Eraxis®)

200 mg IV x 1 dose 100 mg IV q24h

Echinocandin Micafungin (Mycamine®)

None 100 mg IV q24h

Polyene Lipids Amphotericin B

None 3-5 mg/kg IV q24h

CANDIDIASIS

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Most Common

Candida albicans

− Pseudohyphae

Candida glabrata

Candida parapsilosis

Candida tropicalis

Candida krusei

CANDIDIASIS

4/3/2014 35

Broad-spectrum antibacterial agents

Central venous catheters

TPN

Renal replacement therapy

Neutropenia

Implantable devices

Immunosuppressants

CANDIDEMIA – RISK FACOTRS

4/3/2014 36

Persistent signs of infection despite broad spectrum antibacterial agents

Presence of risk factors

Blood culture positive for yeast

– Never a contaminant

– Take time to grow in culture media

CANDIDEMIA – DIAGNOSIS

4/3/2014 37

Increasing incidence of non-albicans isolates

Increasing resistance of C. albicans to fluconazole

Late speciation/ infrequent susceptibility testing

Delayed empiric therapy

PROBLEMS with CANDIDA DISEASE

4/3/2014 38

DELAYED ANTIFUNGAL THERAPY INCREASES MORTALITY

4/3/2014 39 Garey K et al. Clin Infect Dis 2006;43:25-31.

Azole Resistance

Primary or Intrinsic

– Resistant prior to antifungal exposure

– Example: C. krusei resistant to fluconazole

Secondary or Acquired

– Adaptations

– Mutations

– Examples: C. albicans resistant to fluconazole

CANDIDEMIA TREATMENT

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CANDIDEMIA TREATMENT

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Status Drugs of Choice Alternatives

Non-neutropenic Fluconazole 800 mg x 1, then 400 mg QD OR Echinocandin Caspofungin Micafungin Anindulafungin

Lipid Amphotericin B OR Voriconazole

Treatment Duration is at least 14 days after cultures clear and symptoms resolve.

Pappas PG et al. Clin Infect Dis 2009;48:503-535.

CANDIDEMIA TREATMENT

4/3/2014 42

Status Drugs of Choice Alternatives

Neutropenic Echinocandin –Caspofungin –Micafungin –Anidulafungin OR Lipid Amphotericin B

Azoles –Fluconazole –Voriconazole OR Voriconazole

Treatment Duration is at least 14 days

256 patient double-blind trial

Patients randomized to receive

– Anidulafungin 200 mg x1, 100 mg IV q24h

– Fluconazole 800 mg x1, 400 mg IV q24h

Stratified by neutropenia, APACHE II score

Treatment given for 14-42 days

– Could switch to oral fluconazole after 10 days

Combined clinical + microbiologic success

– Anidulfungin 75.6% vs. Fluconazole 60.25%

– Anidulafungin deemed “noninferior”

ANIDULAFUNGIN vs. FLUCONAZOLE in INVASIVE CANDIDIASIS

4/3/2014 43 Reboli A et al. NEJM 2007;356:472-482.

Endophthalmitis

Osteomyelitis

Septic arthritis

CNS infection

Endocarditis, Pericarditis, Myocarditis

Device infection

CANDIDIASIS COMPLICATIONS

4/3/2014 44

ASPERGILLOSIS

4/3/2014 45

Immunosuppression

Examples

– Prolonged neutropenia

– Bone marrow transplant

– Lung transplant

– Primary immunodeficiency

– HIV

ASPERGILLOSIS

4/3/2014 46

ASPERGILLOSIS RISK FACTORS

PROBABLE ASPERGILLOSIS

Risk factors

Clinical manifestations

–Signs and symptoms

–Radiologic evidence

Microbiologic evidence

–Biopsy

–BAL

–Culture

–Histopathology

PROBABLE ASPERGILLOSIS

Microscopy

–Dichotomously branching septate hyphae

Radiology-CT scan

–Halo or air-crescent sign

Serology

–Positive galactomannan assay (platelia)

4/3/2014 47

Drugs of Choice Alternatives Voriconazole Lipid Amphotericin B

OR

Caspofungin

OR

Micafungin

OR

Posaconazole

ASPERGILLOSIS

4/3/2014 48 Walsh TJ et al. IDSA Clinical Practice Guideline. Clin Infect Dis 2008;46:327-360.

Treatment Duration is 6-12 weeks

Prospective, RCT including patients with invasive pulmonary aspergillosis

Interventions

– Voriconazole VS Conventional amphotericin B

Clinical success at 12 weeks

– Voriconazole 53% vs. Amphotericin B 32%- SUPERIOR

– NNT= 5

Survival at 12 weeks

– Voriconazole 71% vs. Amphotericin B 58%

Aspergillosis: Literature

4/3/2014 49 Walsh TJ et al. IDSA Clinical Practice Guidelines. Clin Infect Dis 2008;46:327-360.

Open-label, non-comparative trial of 141 patients

Patients received voriconazole 6 mg/kg q12h x 2 doses, then 3 mg/kg IV q12h, then could switch to 200 mg PO q12h

Successful response defined as complete or partial

Subjects (52%) received voriconazole as primary therapy

VORICONAZOLE Primary and Refractory Invasive Aspergillosis Trial

4/3/2014 50 Denning DW et al. Clin Infect Dis 2004;34:563-571.

VORICONAZOLE Primary and Refractory Invasive Aspergillosis Trial

4/3/2014 51 Denning DW et al. Clin Infect Dis 2004;34:563-571.

VORICONAZOLE Primary and Refractory Invasive Aspergillosis Trial

4/3/2014 52 Denning DW et al. Clin Infect Dis 2004;34:563-571.

VORICONAZOLE: TIME to MONITOR

4/3/2014 53 Purkins et al. AAC 2002;46:2546-53.

Voriconazole has high intra- and inter-patient variability

High concentrations associated with toxicity, low concentrations with failure

VORICONAZOLE: TIME to MONITOR

4/3/2014 54 Gallagher JC. Current Fungal Infection Reports 2009;3:69-76.

339 patients randomized to 3 mg/kg/day or 10 mg/kg/day of LAmB x2 weeks, then 3 mg/kg/day for probable or proven invasive mould infection

Primary endpoint: – Clinical response at end of study drug treatment

Mostly hematological malignancies with neutropenia

201 patients available for analysis

– 107: 3 mg/kg/day – 94: 10 mg/kg/day

AmBisome: What’s the Dose?

4/3/2014 55 Cornely OA et al. Clin Infect Dis 2007;44:1289-1297.

AmBisome: What’s the Dose?

4/3/2014 56 Cornely OA et al. Clin Infect Dis 2007;44:1289-1297.

4/3/2014 57

AmBisome: What’s the Dose?

Cornely OA et al. Clin Infect Dis 2007;44:1289-1297.

47 adults with proven or probable aspergillosis retrospectively evaluated

After failing initial AmBd, patients received voriconazole 6mg/kg x2, then 4mg/kg q12h with or without caspofungin 70mg x1, then 50mg q24h

Endpoint: 3 month survival

Majority had infection after HSCT

Combination Antifungal Therapy Voriconazole vs. Caspofungin + Voriconazole

4/3/2014 58 Marr KA et al. Clin Infect Dis 2004;39:797-802.

4/3/2014 59

Combination Antifungal Therapy Voriconazole vs. Caspofungin + Voriconazole

Marr KA et al. Clin Infect Dis 2004;39:797-802.

4/3/2014 60

Combination Antifungal Therapy Voriconazole vs. Caspofungin + Voriconazole

Marr KA et al. Clin Infect Dis 2004;39:797-802.

CRYPTOCOCCOSIS

4/3/2014 61

HIV/AIDS

– CD4 count < 50 cells/mm3

Immunosuppression

– CKD

– DM

– Malignancy

– Organ transplant

CRYPTOCOCCOSIS

4/3/2014 62

Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. June 18,2008. http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf accessed February 10,2009.

Nonimmunosuppressed

– Primary pulmonary infection

– Cough, rales, SOB

HIV/AIDS

– Meningitis

– Headache, fever, malaise

– Less common: neck stiffness, photophobia, blurred vision, papilledema, seizures, AMS, and aphasia

CRYPTOCOCCOSIS

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CSF

– opening pressure > 20cm H2O

– Mildly protein

– Glucose low to normal

– Lymphocytic

– Positive India ink stain for numerous yeast

– Positive cryptococcal antigen

Positive serum cryptococcal antigen

May have positive blood cultures

CRYPTOCOCCOSIS: DIAGNOSIS

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CRYPTOCOCCAL INDUCTION

4/3/2014 65

Conventional Amphotericin B

0.7-1 mg/kg IV q24h (A-I)

Flucytosine

25 mg/kg/dose q6h (100 mg/kg/day)

First Line Regimen

Alternative: Liposomal Amphotericin B 3-5 mg/kg/day IV q24h (B- II)

14 days

Perfect JR. IDSA Clinical Practice Guidelines. Clin InfectDis 2010;50.

CRYPTOCOCCAL CONSOLIDATION

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Fluconazole

400 mg PO daily 8 weeks

Perfect JR. IDSA Clinical Practice Guidelines. Clin Infect Dis 2010;50.

4/3/2014 67

CRYPTOCOCCAL SUPPRESSION

Fluconazole

200 mg PO daily

At least 12 months

Perfect JR. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Disease Society of America. CID 2010;50. Perfect JR. IDSA Clinical Practice Guidelines. Clin Infect Dis 2010;50.

DIMORPHIC FUNGI HISTOPLASMOSIS

BLASTOMYCOSIS

COCCIDIOIDOMYCOSIS

4/3/2014 68

Acute Infection- Asymptomatic to generalized symptoms

Chronic Pulmonary- Opportunistic infection in patients with structural defects, such as emphysema

– Apical lung lesions granulomas fibrosis

– Chronic symptoms and possible disease progression

Disseminated infection- no improvement after 3 weeks with extrapulmonary involvement

HISTOPLASMOSIS

4/3/2014 69

Acute pulmonary

– Acute infection spectrum of disease varies

– Subclinical → ARDS

Chronic pulmonary

– Symptoms may be similar to TB, other fungal infections or cancer

– Fibronodular interstitial infiltrates on radiologic studies

Extrapulmonary blastomycosis

– Occurs in 20-45% of patients with chronic blastomycosis

BLASTOMYCOSIS

4/3/2014 70

HISTOPLASMOSIS and BLASTOMYCOSIS

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Mild to Moderate

Wheat LJ et al. IDSA Practice Guidelines. Clin Infect Dis 2007;45:807-825.

1 • Itraconazole 200 mg PO TID x 3 days

2 • Itraconazole 200 mg PO BID

4/3/2014 72

HISTOPLASMOSIS and BLASTOMYCOSIS

Severe or Disseminated

1

• Lipid Amphotericin B 3-5 mg/kg/day IV QD x 1-2 weeks

2 • Itraconazole 200 mg PO TID x 3 days

3 • Itraconazole 200 mg PO BID

Wheat LJ et al. IDSA Practice Guidelines. Clin Infect Dis 2007;45:807-825.

Histoplasmosis

Mild to moderate infection

•6-12 weeks

Severe infection

•12 weeks

Disseminated infection

•12 months

Suppression

• Lifelong for immunosuppressed

–Itraconazole 200 mg QD

Blastomycosis

Mild to moderate infection

•6-12 months

Severe and disseminated infections

•6-12 months

4/3/2014 73

TREATMENT DURATION

“Valley Fever”

Acute pulmonary infection

Symptoms similar to CAP

5-10% of infections may have pulmonary sequelae

Disseminated infection

Filipino and African ancestry have higher risk

Immunosuppressed patients

COCCIDIOIDOMYCOSIS

4/3/2014 74 Galgiani JN et al. Clin Infect Dis 2005;41:1217-1223.

Azole antifungals

– Ketoconazole 400 mg PO QD

– Fluconazole 400-1200 mg PO QD

– Itraconazole 200-300 mg PO BID

Amphotericin B

– Deoxycholate (Conventional): 0.5-1.5 mg/kg IV q24h

Therapy results are unpredictable

COCCIDIOIDOMYCOSIS

4/3/2014 75

Itraconazole

– Steady-state achieved around 2 weeks

– Serum concentrations establish efficacy and safety

– Timing of level is not important

– Target > 1.0 µg/mL and < 10.0 µg/mL

– Drug interactions

Amphotericin B

– Scr, Mg, K

– Urine output

– Premedication

MONITORING TREATMENT

4/3/2014 76 Wheat LJ et al. IDSA Guidelines. Clin Infect Dis 2007;45:807-825.

Rapid diagnosis and empiric therapy is key

Echinocandins are first-line options

Micafungin and caspofungin are equivalent

Fluconazole can still be used, but cautiously

Voriconazole has a limited role but is still useful

CANDIDEMIA SUMMARY

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Voriconazole is the first-line agent

– Monitoring should be performed

LAmB dosing: no benefit to high doses?

Combination therapy: is this the way of the future?

Most important factor: immune status of the host

Invasive Aspergillosis Summary

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4/3/2014 79

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