ANTI-FUNGALS
FUNGAL ORGANISMS
Classifications:
Primary – infects immunocompetent Cryptococcus
Histoplasma
Blastomyces
Coccidoides
Opportunistic – infects immunocompromised Candida
Aspergillus
Cryptococcus
Mucor
Candida species:
There are over 150 species of Candida, but only about 15 of these are known to cause infections. The most common species that cause infections
are C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei.
Tidbits:
C. albicans is the most cause of candidemia
Fluconazole-resistant: some C. glabrata isolates (↑ resistance), all C. krusei isolates
Minimal inhibitory concentrations for C. Parapsilosis with echinocandins are higher than for other Candida sp.
Risk factors for resistant Candida sp.: neutropenia, recent azole or other antifungal exposure, chronic renal disease, chronic lung disease,
male gender
Pathogenesis:
Healthy humans are NOT ideal hosts for fungal pathogens
Intact skin and mucosa = physical barriers
Competitive inhibition with normal bacterial flora
pH and body temperature inhibits fungal growth
Cellular immune response eradicates fungal pathogens
Fungal vs. Human Cell
Older anti-fungals have more toxicity due to less specific targets to
fungal cell wall (which are similar to humans)
Yeast Oval, unicellular
Budding
Candida spp.
Cryptococcus spp.
Mould Multicellular, filamentous
Branching
"Looks like dandelions"
Aspergillus spp.
Fusarium spp.
Mucor spp.
Rhizopus spp.
Dimorphic Yeast in host
Mould in envionment
Histoplasma spp.
Blastomyces spp.
Coccidiodes spp.
Risk Factors:
Impaired physical barrier (direct access) – e.g. IV catheterization,
parenteral nutrition, surgery, (Px may ↓ risk of invasive fungal infections but
not mortality), HD/PD
Use of broad spectrum antibiotics
Impaired immune response – e.g. chemotherapy, immunosuppressants,
HIV, neutropenia
Extremes of age
Anti-fungal agents:
I. Polyenes:
Mechanism of Action Destabilize fungal cell membrane by binding ergosterol → leading to leakage of intracellular ions and macromolecules
Antifungal effect Fungicidal
Agents Amphotericin B Nystatin (not used systematically d/t toxicity)
Use Invasive fungal infections Oral candidiasis; Vulvovaginal candidiasis
a. Amphotericin B
Spectrum of Activity Yeast and mould including Candida and Aspergillus
Absorption Poor oral absorption Given IV
Distribution CSF: 2-3% Primarily stored in the kidneys and slowly released resulting in long terminal half-life...∴ d/t high levels in kidney = potential to cause renal toxicity
Metabolism Renal
Elimination Eliminated in urine and bile Terminal half-life = 15 days
Usual dosage AmBd: 0.3-1.5mg/kg IV daily LAmB: 3-6mg/kg IV daily
Toxicity - Highly nephrotoxic after prolonged use. Leads to hypoMg, hypoK and eventually renal tubular acidosis - Infusion reactions – common; leading to fever, headache and hypotension. Can be attenuated through pre-treatment with antipyretics, antihistamines and slowing of infusion rate
Managing Toxicity 1. Adequate hydration with NS prior to infusion 2. Replace electrolytes as needed 3. Use least nephrotoxic formulation available, if possible 4. Consider pre-treatment in beginning with benadryl and tylenol…and as more stable for future infusions, may be able to take away pre-treatments Monitor: LFTs, sCr, Lytes (Kg, Mg)
Formulations:
Liposomal Amphotericin B (LAmB)
o ↓ nephrotoxicity compared to AmBD
o ↓ incidence of infusion reactions
o Expensive
Amphotericin B deoxycholate (AMBd)
o Highly nephrotoxic – limited use
o Inexpensive
o Least restricted on formulary at VGH
Amphotericin B Lipid Complex (ABLC)
o ↓ nephrotoxicity compared to AmBd
o ?↓ incidence of infusion reaction
o Expensive
Amphotericin B Colloidal Dispersion (ABCD)
o ↓ nephrotoxicity compared to AmBd
o ?↑ incidence of infusion reaction
o Expensive
Clinical tidbit: Renal dysfunction with deoxycholate – don't hold back on dosing since it is not eliminated renally but may ↓ dose every 2nd
day or give
patients a break since the issue is that it "causes" nephrotoxicity
Used generally 1st
line in VGH and other BC sites due to concerns
with nephrotoxicity, regardless of baseline renal function…but
VGH formulary supports deoxycholate as the 1st
line formulation
d/t high cost and limited evidence surrounding efficacy of lipid
formulations…unless patients have kidney dysfunction or a
documented intolerance to Amphotericin B deoxycholate
II. Nucleoside Analogue - Flucytosine
Mechanism of Action Taken up by fungal cell via cytosine permease and converted to active metabolites that inhibit DNA and RNA synthesis
Antifungal effect Fungistatic
Agents Flucytosine
Use *SAP* Combination with AmpB for cryptococcal meningitis
Toxicity Bone marrow suppression, GI upset, enterocolitis, hepatotoxicity
Spectrum of Activity Cryptococcus neoformans, Candida spp. (except C. Krusei)
Absorption Excellent oral absorption (>90%)
Distribution All body fluid compartments CSF: 60-100%
Metabolism Hepatic (possibly deaminated by gut flora to 5-FU) → theory as to where bone marrow suppression and GI intolerance comes from
Elimination Eliminated in urine (>90% unchanged drug) Half-life = 2-5 hours
Usual dosage 25mg/kg PO q6h *must renally adjust*
III. Imidazoles
Mechanism of Action Inhibit fungal CYP lanosterol demethylase synthesis of ergosterol → destabilized cell membrane and accumulation of toxic sterols
Antifungal effect Fungistatic
Agents Ketoconazole, Miconazole, Clotrimazole
Use Topical for superficial yeast/dermatophyte infections
IV. Triazoles
Mechanism of Action Inhibit fungal CYP lanosterol demethylase synthesis of ergosterol → destabilized cell membrane and accumulation of toxic sterols
Antifungal effect Fungistatic (yeast) Fungicidal (Aspergillus)
Agents Fluconazole, Voriconazole, Itraconazole, Posaconazole, Isavuconazole
Use Invasive fungal infections including candidemia and aspergillosis
a. Fluconazole
Spectrum of Activity Candida spp. (except C. Krusei), C. Neoformans, C. Immitis, B. Dermatidis, H. Capsulatum If report as sensitive to Candida, but it is in a place that is difficult to penetrate, it would be good to call and ask about MIC
Absorption Excellent oral absorption (90%)
Distribution All body fluid compartments CSF: 50-60%
Metabolism Minimally CYP3A4
Elimination Eliminated primarily unchanged in urine Half-life = 30 hours
Interactions CYP 2C9, 2C19, 3A4 inhibitor
Usual dosage 100-800mg IV/PO daily *must renally adjust* 100-400mg PO daily
Use Candidemia not caused by C. krusei or resistant C. glabrata, vulvovaginal candidiasis, esophageal candidiasis, chronic suppressive therapy following cryptococcal meningitis
b. Voriconazole
Spectrum of Activity Candida, Aspergillus
Absorption Excellent oral absorption (95%)
Distribution All body fluid compartments CSF: 22-100%
Metabolism Hepatic; CYP2C9, 2C19, 3A4 Non-linear kinetics
Elimination Eliminated primarily unchanged in urine Half-life = 30 hours
Interactions CYP 2C9, 2C19, 3A4 inhibitor
Usual dosage IV/PO: 6mg/kg q12h x2 then 4mg/kg q12h
Use Aspergillosis Disseminated candidiasis Candidemia
c. Itraconazole – role is limited due to moderate F, poor distribution…but has a broad spectrum of activity and may serve as salvage therapy for
patients who have not recovered on other azoles
Spectrum of Activity Candida (except C. krusei), C. Neoformans, C. immitis, B. Dermatitidis, H. Capsulatum
Absorption Moderate (50%)
Distribution Poorly distributed to body fluids CSF: 10%
Metabolism CYP 3A4
Elimination Hepatic Half-life = 24 hours
Interactions CYP 2C9, 3A4 inhibitor
Use Blastomycosis Coccidioidomycosis Histoplasmosis Sporotrichosis Aspergillosis
d. Posaconazole – "improved version of itraconazole"
Spectrum of Activity Candida, Cryptococcus, Coccidoides, Histoplasmosis, Blastomyces, Zygomycetes
Absorption 54%, with food
Distribution Moderately distributed Therapeutic levels in CSF
Metabolism Minimal hepatic
Elimination Eliminated primarily unchanged in urine Half-life = 25 hours
Interactions CYP3A4 inhibitor
Usual Dosage Suspn: Tx: 400mg bid or 200mg qid; Px: 200mg tid DR tabs: Tx and Px: 300mg bid x2 then 300mg daily
Use Prophylaxis of invasive fungal infections in neutropenic patients Refractory invasive fungal infections Zygomycetes
e. Isavuconazole (SAP) – new agent ∴ not as much information regarding pharmacokinetics…can be considered as salvage therapy where patients
have not improved on other azoles (costly and a "me-too" drug)
Spectrum of Activity Candida, Cryptococcus, Coccidoides, Histoplasmosis, Blastomyces
Absorption Excellent oral absorption (98%)
Distribution All body fluid compartments CSF: ?
Metabolism Hepatic, CYP3A4
Elimination Eliminated in urine and feces Half-life = 130 hours
Interactions CYP2C9, 2C19, 3A4 inhibitor
Use Mucormycosis (2nd
or 3rd
line – salvage/intolerance) Aspergillosis (2
nd or 3
rd line)
Drug interactions summary for Triazoles:
V. Echinocandins
Mechanism of Action Disrupts fungal cell wall by inhibiting β 1,3-D-glucan synthesis → osmotic lysis
Antifungal effect Fungistatic (Aspergillus) Fungicidal (Candida)
Agents Capsofungin, Micafungin, Anidulafungin
Use Parenteral for invasive fungal infections including candidemia and aspergillosis
Toxicity Flushing, GI upset – generally well tolerated
a. Capsofungin
Spectrum of Activity Candida (except parapsilosis), Aspergillus
Absorption Poor – only IV
Distribution 97% protein bound, well into tissue, no CSF penetration
Metabolism Hepatic – hydrolysis and N-acetylation Spontaneous degradation
Elimination Urine and feces as metabolites Half-life = 9-11 hr Don't have to be concerned with renal dose adjustment
Interactions ↑ LFT with cyclosporine
Use Candidemia and other disseminated candidal infections Esophageal candidiasis Invasive aspergillosis (as salvage) Empiric anti-fungal coverage in febrile neutropenia
b. Micafungin
Spectrum of Activity Candida (except parapsilosis), Aspergillus
Absorption Poor – only IV
Distribution 99% protein bound, well into tissue – liver, lung, spleen, no CSF penetration
Metabolism Hepatic
Elimination Feces; Half life = 11-21 hr
Interactions May ↑ levels of nifedipine, sirolimus, cyclosporine
Usual Dosage Candidemia: 100mg IV daily Px: 50mg IV daily Esophageal Candidiasis: 150mg IV daily
Use Candidemia and disseminated candidal infections Esophageal candidiasis Prophylaxis of candidal infections in HSCT patients
c. Anidulafungin
Spectrum of Activity Candida, Aspergillus
Absorption Poor – only IV
Distribution 99% protein bound, well into tissue, no CSF penetration
Metabolism Chemical hydrolysis – no hepatic metabolism
Elimination Feces (<10% as unchanged drug)
Half-life = 24-48 hrs
Interactions None observed
Use Candidemia and disseminated candidal infections Esophageal candidiasis
Spectrum of Activity
Cost and Availability
F: Formulary
Summary of mechanism of action: Summary of toxicity:
INFECTIONS
I. Cryptococcal Meningitis
Organism Yeast – C. Neoformans (opportunistic; associated with bird droppings) or C. Gattii (found in soil and can infect immuno-competent pts)
Risk Factors Immunodeficiency
Source Environmental – soil, decaying wood, bird droppings
Diagnostic CSF culture, India skin stain, serum/CSF cryptococcal Ag CSF fluid, high WBC (mononuclear predominance), low glucose, normal/high protein
Treatment Induction: AmpB + 5-FC Consolidation/Maintenance: Fluconazole
Guidelines are for neoformans (and these guidelines are extrapolated to gattii)
HIV Non-HIV Transplant
Induction AmBd 0.7-1mg/kg/day IV + 5-FC 25mg/kg PO q6h LAmB 3-4 mg/kg/day IV or ABLC 5mg/kg/day IV + 5-FC 25mg/kg PO q6h x 2 weeks
X 2 weeks X 4-6 weeks (Poor outcomes for
2 wks, longer tx possibly d/t concern that immunocompetent pt was infected with an opportunistic organism)
Consolidation Fluconazole 400mg/day x 8 weeks Fluconazole 400-800mg/day x 8 weeks
Maintenance Fluconazole 200mg/day x 6-12 months Fluconazole 200-400mg/day x 6-12 months
Combination therapy recommended with AmB + 5-FC
o AmB causes "holes in cell wall" and enhances penetration of 5-FC and prevents its efflux
o RCT evidence has shown combination results in:
↑ cure/clinical improvement rates
↓ failure/relapse
faster CSF sterilization
less nephrotoxicity
Generally extend induction if high risk, complicated or not using 5-FC
Dose adjust AmBd, 5-FC, fluconazole for renal function
AmBd + 5-FC vs. AmBd + Fluc: Better 14 day mortality with 5-FC, NSS with 90 day mortality
An ID doctor at VGH recommends life-long maintenance treatment since it is difficult to get CSF penetration and truly sterilize the CNS. Risk
of low-dose fluconazole is low…has also encountered refractory cases and generally life prognosis with this infection is not very long
II. Aspergillosis
Organism Mould
Risk Factors HSCT, SOT, HIV/AIDS, other immunodeficiencies including chronic glucocorticoid use
Diagnosis Molecular assay, culture and cytology, histopathology At VGH – molecular assay is more of a diagnostic tool and have poor results ∴ if high risk pt, CT looks like invasive aspergillosis (looks like fungal ball), would do a bronchoscopy and send otu fluid for galactomannan assay which has high specificity and sensitivity here
Treatment Initial: Triazoles, Amphotericin B Salvage: Echinocandins
Initiating Therapy Empiric initiation warranted in high risk patients with suspicion for IA, do not await diagnostic results
Monitoring TDM of triazole/imidazole therapy Serial galactomannan assays may be considered to monitor patient response
Voriconazole vs. Amphotericin B: immunocompromised pts with definite or probable invasive asperigllosis, ↑ 12 week survival with
voriconazole…but failure of amphotericin was more due to treatment intolerability (vs. Clinical failure)
Insufficient evidence to support combination therapy of voriconazole + anidulafungin
Invasive Pulmonary Aspergillosis:
First-Line Alternative
Voriconazole IV Load: 6mg/kg x 2 doses Maintenance: 4mg/kg x 6-12 wks (strong recommendation)
Liposomal AmpB (LAmB) (strong recommendation) Isavuconazole (strong recommendation) Other AmpB formulations (weak recommendation) Salvage Therapy: Posaconazole, Itraconazole or Echinocandin
Extra pulmonary Aspergillosis
Syndrome First-Line Alternative
CNS Aspergillosis Voriconazole IV (better penetration than AmpB) AmB formulations (strong recommendation) - Deoxycholate = poor CNS penetration, Liposomal may have better CNS penetration - Echinocandins = large molecules ∴ difficult to cross through CNS and won't use for CNS infections
Endopthalmitis Voriconazole IV/PO + intravitreal injection - Voriconazole has ~40% penetration into vitreous fluids and can get good concentration in eyes for eye infections
Cutaneous/Gastrointestinal Aspergillosis
Voriconazole IV
Osseous/Cardiac/Paranasal Surgical resection
Aspergillosis Prophylaxis:
Recommended in patients expected to experience prolonged neutropenia (HSCT, GVHD, SOT) in patients at high risk for invasive
aspergillosis
First Line Posaconazole (strong recommendation)
Second Line Voriconazole (strong recommendation), Micafungin (weak recommendation)
Second Line – Lung transplant only Inhaled amphotericin B
III. Candidemia:
Organism Yeast – C. albicans historically most common, C. glabrata emerging
Risk Factors Abdominal surgery, GI perforation, anastomic leak, colonization, acute necrotizing pancreatitis, long ICU sty (>15 ds?), CVC< use of broad spectrum Abx, immunodeficiency, neonates (low birth weight, preterm)
Source Normal flora on skin, GIT and female genital tract
Diagnosis Culture, B-D-glucans, Candida mannan Ag/anti-mannan Ab
Treatment Non-neutropenic: Echinocandins, selective fluconazole (if Candida spp. hasn't speciated yet, there may be a risk that it is not susceptible to fluconazole) Neutropenic: Echinocandin, LAmB
Treatments:
First-line Alternative
Non-neutropenic Echinocandin (e.g. micafungin 100mg daily) Fluconazole 800mg LD then 400mg daily
- can be considered for specific pts who are stable and low risk of resistance
AmB
Neutropenic Echinocandin (e.g. micafungin 100mg daily) LAmB 3-5mg/kg daily
Voriconazole added for added mold coverage Fluconazole
1st
line – Echinocandins! Candida – slower growing so it takes longer to be speciated and even longer for sensitivities to come back…very little risk to
switch to echinocandin and higher mortality with delay in appropriate treatment (40% mortality with candidemia)…can consider step down to
voriconazole when appropriate and sensitivites have not returned as it will cover C. Krusei and C. Glabrata (vs. fluconazole)
Treat x 2 weeks after negative BCx and Sx/neutropenia resolve – can step-down to fluconazole or voriconazole if clinically stable and
susceptible isolate
Generally only consider fluconazole if clinically stable and low likelihood resistant organism
Combination therapy?: Insufficient evidence to support combination therapy of fluconazole + AmBd
Anidulafungin vs. Fluconazole: NSS all-cause mortality, Tx success (resolution of s/s and negative Cxs) diff of 3.9-27% favouring
anidulafungin
Micafungin vs. LAmB: NSS mortality, difference of 0.1% in Tx success, higher incidence of AEs with LAmB
Fluconazole vs. AmBd: In + Candida (excl. ANC < 0.5, hematologic malignancy, immunodeficiency, etc.), NSS in Tx success and all-cause
mortality, higher risk of ↑ BUN or sCR and ↓ K+ with AmBd
Therapeutic Drug Monitoring:
Rationale:
many antifungal agents are associated with significant toxicities (nephrotoxicity, bone marrow suppression) and have many drug
interactions
variability in pharmacokinetic parameters like absorption and metabolism make standard dosing estimates challenging
majority of invasive fungal infections occur in patients on multiple medications
Drug Flucytosine Voriconazole non-linear kinetics + multiple DIs
Posaconazole 2 formulations: PO tab (absorbed better), IV (available but not on formulary), suspension (poor F)
Target 20-50mcg/mL 1-5mcg/mL 0.72-1.25mcg/mL >0.72 – for prophylaxis and "higher levels" for treatment
Timing 2 hours post dose Trough Trough
Frequency 1-2 times weekly Once after 5 days …then weekly until therapeutic x 2 – repeat if changes or concerned about efficacy or safety
Until target Css achieved
Posaconazole and voriconazole levels need to be sent to SPH (done once per week)
SPH usually has supply of 5-FC and usually able to get it from them