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
4/3/2014 12
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
4/3/2014 13
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
4/3/2014 22
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
4/3/2014 23
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
4/3/2014 24
Pharmacokinetic
– Well absorbed, hepatically metabolized
– Non-linear
– SBECD of IV form is renally eliminated
Adverse Events
– Visual effects
– Hepatotoxicity
– Visual hallucinations
Drug interactions
VORICONAZOLE
4/3/2014 25
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
4/3/2014 26
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
4/3/2014 28
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
4/3/2014 30
Pharmacokinetic
− Poor bioavailability
− Well distributed
− Variable metabolism
− Not eliminated renally
Pharmacodynamic
− Concentration-dependent
Adverse Events
− Hepatotoxicity
− Infusion-related reactions
− Phlebitis
Expensive
ECHINOCANDINS
4/3/2014 31
ECHINOCANDINS
4/3/2014 32
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
4/3/2014 33
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
4/3/2014 34
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
4/3/2014 40
CANDIDEMIA TREATMENT
4/3/2014 41
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
4/3/2014 63
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
4/3/2014 64
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
4/3/2014 66
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
4/3/2014 71
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
4/3/2014 77
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
4/3/2014 78
4/3/2014 79
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