31/32 - AntiFungals Flashcards
What type of fungi?
Yeast w/ Large Capsule
- *Cryptococcus**
- neoformans*
What type of fungi?
Acute Angle Branching Hyphe
ASPERGILLUS
What type of fungi?
Normally in CAPSULE –> burst out
COCCIDIODES Immitis
(BURST OUT)
Dimorphic Fungi
What FUNGAL FORM?
UniCellular
single cells / spherical / rigid cell wall
Round/Oval, Smooth + Flat colonies
that reproduce by:
BUDDING
Candida** + **Cryptococcus
UniCellular
single cells / spherical / rigid cell wall
Round/Oval, Smooth + Flat colonies
that reproduce by:
BUDDING
What FUNGAL FORM?
Filamentous
Filaments called Hyphae, collectively = Mycelium
Appear:
Fuzzy / Growth through BRANCHING
MOLDS
Aspergillus** + **Mucor** + **Fusarium
What FUNGAL FORM?
Exists as YEAST or MOLD
Dependent on environment
Yeast > 37*C
Mold = Environment
DIMORPHIC
Blastomyces Dermatitdis
Cocciodiodes (burst)
Histoplasma Capsulatum
- *Candida Susceptabilities:**
- *What ANTIFUNGAL** has activity against:
C. Albicans** & **C. Tropicalis
ALL ANTIFUNGALS
- *Candida Susceptabilities:**
- *What ANTIFUNGAL** has activity against:
C. Parapsilosis
All Antifungals:
EXCEPT
ECHINOCANDINS = S-R
Caspofungin / Micafungin / Anidula fungin
- *Candida Susceptabilities:**
- *What ANTIFUNGAL** has activity against:
C. Glabrata
FLUCYTOSINE** + **EchinoCandins
S-Intermediate = Amphotericin
S-DD-R = Itraconazole
- *Candida Susceptabilities:**
- *What ANTIFUNGAL** has activity against:
C. Krusei
- *ESCHINOCANDINS**
- fungins
Resistant to FLUCONAZOLE
S-DD-R = Itraconazole
- *Candida Susceptabilities:**
- *What ANTIFUNGAL** has activity against:
C. Lusitaniae
ALL antifungals EXCEPT:
AMPHOTERICIN B
only S-R
Which Antifungal MoA?
Forms aggregates in cell membrane w/ ERGOSTEROL
Leading to:
Pores that cause leakage of cellular contents
AMPHOTERICIN B
Liposomal / Lipid-Complex / deoxycholate
Which Antifungal MoA?
BLOCK biosynthesis of ergosterol,
sterol needed for cell-membrane stability
VIA
Fungal CYP450 Inhibition
TRIAZOLES
Fluconazole + Voriconazole
Itracanozole + Ketoconazole
Posaconazole + Isavuconazole
Which Antifungal MoA?
DISRUPT function of the (1->) B-D-Glucan Synthase Complex
ECHINOCANDINS
Anidula-fungin
Mica-fungin
Caspo-fungin
Which Antifungal MoA?
Disrupts fungal RNA & DNA Syntheis
5FUTP & 5FdUMP
- *FLUCYTOSINE**
- *5-FC**
Which antifungals require TDM
THERAPEUTIC DRUG MONITORING
- *AZOLES**
- *Itra**conazole + Voriconozole + Posaconazole
- except FLUCONAZOLE*
FLUCYTOSINE
What ANTIFUNGALs can be used in
PREGNANCY?
- *AMPHOTERICIN B**
- *DOC for Invasive Candidiasis** in Pregnancy
- can’t use AZOLES except…*
- *Fluconazole 150mg x1 dose**
Which ANTIFUNGALs require
RENAL DOSING?
FLUCYTOSINE
Primarily as adjuvent in cryptococcal meningitis
FLUCONAZOLE
Fluconazole = 80% renal elimination
is also why..
GOOD URINARY PENETRATION –> for Urinary Infections
Which ANTIFUNGAL requires
HEPATIC Dose ADJUSTMENT?
VORICONAZOLE
Dose adjust ment in Mild-Moderate Liver Dysfunction
CP Class A/B–>std LD –> 50% MD
CASPOfungin
Requires adjustment in Chronic Liver Disease
Tacro + Rifampin
Dosing Considerations
Amphotericin B
- no dose adjustment for renal/hepatic*
- *NEPHROTIXIC**
- may reduce if toxicity occurs*
- *Dosing based on FORMULATION**
- Liposomal vs Lipid Complex vs Deoxycholate** (lowest dose)*
- *Total Body Weight**
Amphotericin B
ADR / Drug Interactions / Monitoring
LIPID FORMULATIONS = less ADR
vs deoxycholate
NEPHROTIXIC + Electrolyte Wasting Mg/K
Infusion-Related Reactions
3-5 days = fevers / chills / rigors
premedicate w/ hydrocortisone
DIGOXIN –> hypoKalemia
Monitor:
Creatinine / Urine Output / K / Mg / LFT / Ca
Itraconazole
Spectrum
Endemic Fungi
most commonly used for HISTOPLASMA CAPSULATUM
- *S-DD-R** for C. Glbrata & C. Krusei
- dose dependent susceptibility*
Aspergillus
Itraconazole
Dosing Consideration
TDM vis HPLC + Loading Dose
Capsules:
- *MEAL +/- ACIDIC ENVIRONMENT**
- do NOT use PPI or H2RA*
Solution:
fine to be fastig
Itraconazole
ADR / DI / Monitoring
ADR:
- Peripheral Neuropathy** ↑LFT *_hypokalemia_
- *Negative Inotropic Activity**
DI:
CYP3A4 Substrate + Inhibitor
PPI**+**H2RA
CI w/ STATINS (except pravastatin)
Monitoring:
LFT / S/Sx CHF / Rash
Fluconazole
Spectrum
RESISTANT to C. KRUSEI
DD-R for C. Glabrata
Cryptococcus (Capsule Yeast)
Endemic Fungi
Fluconazole
Dosing Considerations
no TDM
- *Loading Dose Required**
- *double dose for C. Glabrata** in Invasive Candidiasis
RENAL DYSFUNCTION DOSAGE ADJUSTMENT
80% renally eliminated
Fluconazole
ADR / CI / Monitoring
ADR:
Well tolerated - NV - ↑LFT - HA - Reversible Alopecia
CI:
weak inhibitor of CYP450, none
Monitoring:
LFTs / Rash / QT interval in high risk pts
Voriconazole
SPECTRUM
ASPERGILLUS Spp
DOC
Fusarium** + **Scedosporium
- not fully susceptable = S-R for*
- *C. Glabrata** & C. Krusei
Voriconazole
Dosing Considerations
TDM** + **Loading Dose
DOSE ADJUSTMENT for LIVER DYSFUNCITON
Child Pughs A/B
std LD –> 50% MD
Which ANTIFUNGAL has
serious / a lot of ADRs
VISUAL DISTURBANCES
photopsia hallucinations
VORICONAZOLE
Need to monitor:
VISUAL FUNCTION
Renal function / Bilirubin / LFT
Voriconazole
ADR / CI / Monitoring
A LOT OF ADR:
VISUAL DISTURBANCES (photosphisa / hallucinations)
HEPATOTOXICITY
Peripheral Neuropathy
Prolonged QT & TDP (torsades)
DI:
CYP2C19 Metabolism
Monitoring:
↑LFT / Bilirubin / Renal Fxn / Visual Function
Posaconazole
SPECTRUM
MUCOR
one of the few who have this activity
Aspergillus** + **Endemic Fungi
- some resistance S-R to:*
- *C. Glabrata + C. Krusei**
Posaconazole
Dosing Considerations
TDM** + **Loading Dose
SUSPENSION:
ACIDIC ENVIRONMENT**+**HIGH FAT MEAL
no dose adjustments, no longer used
- *DELAYED RELEASE TABLET**
- *IMPROVED ABSORPTION > Suspension**
Posaconazole
ADR / CI / Monitoring
ADR:
Similar to Fluconazole
DI:
- not CYP metabolism but* affected by : Rifabutin / Phenytoin
- Inhibits CYP3A4* / ↑Cyclosporin
Monitoring:
PO Intake / Diarrhea
LFTs / Bilirubin / K / Mg / Ca
Isavuconazole
SPECTRUM
Indicated for:
Invasive ASPERGILLOSIS** + **MUCORmycosis
- some resistance S-R to:*
- *C. Glabrata + C. Krusei**
Cryptococcus + Scedosporium + Endemics
Isavuconazole
Dosing Considerations
TDM** + **PRODRUG
Requires LOADING DOSE
Isavuconazole
ADR / CI / Monitoring
ADR:
- less ADR* vs Voriconazole
- *Nusea / Hepatotoxicity** / CNS = AMS + Seizure
DI:
- *Inhibitor + Metabolized by CYP3A4**
- *Mild P-GP inhibitor**
Monitoring:
LFTs / K / Mg
Echinocandins -fungins
Spectrum
FungiCIDAL
Primary role:
- *CANDIDA** (including Azole-Resistants)
- except for C. Parapsilosis (S-R)*
Aspergillus
less ectivity vs Fusarium / Cryptococcus
EchinoCandins
Dosing Considerations
IV ONLY
- *CASPO + ANIDULA** = Require LOADING DOSE
- MICAfungin does NOT need LD*
CASPOFUNGIN needs HEPATIC adjustment
Child-Pughs 70mg LD –> 35mg/day (instead of 50)
Which Echinocandin(s) require
DOSE ADJUSTMENT in CHRONIC LIVER DISEASE?
CASPOfungin
based on Child-Pughs
70mg LD –> 35 mg MD (vs 50mg MD)
Which Echinocandin(s) require
LOADING DOSE?
CASPOfungin** + **ANIDUAfungin
loading dose needed
- micafungin*
- does NOT need LOADING DOSE*
Which Echinocandin has a
DRUG INTERATION?
and with what?
CASPOfungin
also requires hepatic dose adjustment
↓Tacrolimus Concentrations
Rifampin –> ↓Caspo Concentration via OATP1B1
requires:
↑Caspo Dose to 70mg QD w/ Rifampin and others:
phenytoin / carbamazepime / efavirenz / nevirapine
EchinoCandins
ADR / Monitoring
no drug interactions
EXCEPT for CASPOfungin = rifampin
↑LFTs
Monitor:
CBC & LFT
Flucytosine = 5-FC
SPECTRUM
Primarily as:
- *ADJUVENT_ in _CRYPTOCOCCAL MENINGITIS**
- not used on its own*
- *Candida Activity**
- except C. Krusei*
Flucytosine 5-FC
Dosing Consideration
100-150 mg/kg/day IV/PO in four divided doses
RENAL DOSING ADJUSTMENT
requires:
TDM
+ not given as monotherapy
Flucytosine 5-FC
ADR / CI / MOnitoring
ADR:
Rash / Diarrhea / LIVER toxicity
HEMATOLOGIC TOXICITY
Monitor:
CBC / Creatine / urine
LFT / Serum Levels
Which antifungal is
CONTRAINDICATED with STATINS?
ITRACONAZOLE
CI w/ statins except PRAVAstatin
Also avoid:
PPI + H2RA
CYP3A4 Substrate + Inhibitor
Risk Factors for
Candidiasis
Use of:
Broad Spectrum ABx
Central Venous Catheters** + **TPN
Dialysis / Neutropenia / IMS
Recent ItraAbdominal SURGERY
Prosthetic Devices
Colonization @multiple sites (urine)
Candidiasis
Empiric Treatment + Duration
ECHINOCANDINS
Especially if patient is:
Critically Ill / RECENT AZOLE / Neutropenia
2 WEEKS
starting from 1st negative blood culture or SOURCE CONTROL
Can step down from Echinocandins:
Fluconazole 800mg LD –> 400mg QD
Which Fungal Infection?
Commonly from:
- *CATHETER** or GI source
- remove central venous catheter if possible*
Fundoscopic Exam –> EYE
Mouth = Thursh
Vulvovaginal
Urine
CANDIDIASIS
Candida = Budding ROUND Yeast
If in BLOOD = CANDIDEMIA
treat ASAP <12 hours = best mortality
Which Fungal Infection?
Universal Exposure –> INHALATION
Presents as:
Invasive Pulmonary / Bronchopulmonary / CNS
Risk Factors:
Prolonged Neutropenia ANC < 100
Hematologic Malignancy / Steroid Use
AML / BMT / SOT (lung esp)
- *ASPERGILLOSIS**
- *Acute Angle Septate BRANCHING**
Common Species:
A. FUMIGATUS > A. Flavus > A. Niger
Aspergillosis
DIAGNOSIS
DIFFICULT to Diagnose
- *Biopsy = Definitive**
- but difficult to do and INVASIVE*
GALACTOMANNAN = Specific
in high risk population
Beta-D Glucan = NONspecific
- *CT IMAGING**
- *HALO SIGN** - nodules / wedge shaped legions
Aspergillosis
TREATMENT
VORICONAZOLE
1st line
Isavuconazole = 2nd line
Other agents w/ Activity:
Amphotericin / Echinocandins
Which Fungal Infection?
Mainly affects:
Immunocompromised / AIDS patients
Presents as:
Meningitis / Pneumonia
Culture shows:
CAPSULE
- *CRYPTOCOCCAL DISEASE**
- *CAPSULE one**
Diagnosed with:
Cryptococcal Antigen Culture
Which Fungal Infection?
Commonly presents as:
Pulmonary Disease
IMS patients –> disseminated histoplasmosis in GI tract
Endemic / Dimorphic –> Certain Areas
Can be found in SOIL / Avian Droppings
Can disseminate anywhere:
CNS / Skin / Bone
DIMORPHIC FUNGI
ENDEMIC DISEASE
Specific Fungus depends on GEOGRAPHIC AREA
CRYPTOCOCCAL DISEASE
CAPSULE one
Treatment
Meningitis Treatment:
AMPHOTERICIN B** + **FLUCYTOSINE for 2 Weeks
then….
Fluconazole 400mg QD –> 8 Weeks
then
Fluconazole 200mg/day –> > 1 YEAR
- *IRIS CONSIDERATION**
- -> DEFER ART for 5 weeks POST TREATMENT
Dimorphic Fungi (Endemics)
INDUCTION TREATMENT
for
Severe Disease
for SEVERE disease:
AMPHOTERICIN B
vvv
May step down / consolidate therapy with triazole
Dimorphic Fungi (Endemics)
Non-Severe Treatment
Histoplasma Capsulatum
ITRACONAZOLE
Dimorphic Fungi (Endemics)
Non-Severe Treatment
Coccidioides Spp
ITRACONAZOLE
Dimorphic Fungi (Endemics)
Non-Severe Treatment
Blastomyces Dermatitidis
Fluconazole = CNS
Voriconazole** or **Itraconazole
Which Fungal Infection?
Commonly presents as:
Invasive Sinus** / **Rhinocerebral disease
w/ Rapid Tissue necrosis
- *Facial Pain / Unilateral HA / Drainage / Tissue sWELLING**
- pulmonary / cutaneous / disseminated = LESS common*
- *ZYGOMYCOSIS**
- *Mucor / Mucormycosis / Rhizopus**
Found in:
Environment / DECAYING matter
- *ZYGOMYCOSIS**
- *Mucor / Mucormycosis / Rhizopus**
RISK FACTORS
Found in:
Environment / DECAYING matter
Long-Standing IMS state
or
Uncontrolled DIABETES
TRAUMA / DEFEROXAMINE
ZYGOMYCOSIS
Mucor / Mucormycosis / Rhizopus
TREATMENT
Primary Treatment:
SURGERY** + **restoration of immune system
Other Treatment:
Amphothericin B** or **Posaconazole** or **Isavuconazole
may combine 1 of above w/
Echinocandin
HIGH MORBIDITY / MORTALITY TREAT RIGHT AWAY = SURGERY
