antifungals Flashcards
what type of fungal infections are life threatening
systemic infections
what populations are often affected by fungal infections
immunosuppressed
chronic immune suppression
undergoing chemotherapy
HIV/AIDS
etc
what are the superficial fungal infections
pityriasis versicolor
tinea nigra
what are cutaneous fungal infections
dermatophytosis (skin, hair and nails) (tineas)
candidiasis of skin (breast, armpits, inguinal folds)
what are subcutaneous fungal infections
sporotrichosis (rose-gardeners)
chromomycosis
what are systemic fungal infections
coccidioidomycosis
histoplasmosis
blastomycosis
cryptococcosis
systemic candidiasis
aspergillosis
zygomycetes (mucorales)
what are the different categories of antifungal drugs
Polyenes
Zadoles
Echinocandins
allylamines
other
what are the polyene antifungal medications
amphotericin B
Nystatin (potent)
what are the Zoles antifungal medications
clotrimazole
ketoconazole
fluconazole
itraconazole
posaconazole
posaconazole
voriconazole
what are echinocandin medications
caspofungin
what are allylamines
terbinafine
what are the other antifungal drugs
flucytosine
griseofulvin
what is the MOA for amphotericin B
lipophilic rod-like molecule disrupts fungal cell wall synthesis by binding to sterols, primarily ergosterol, leading to formation of pores in the cell membrane. K+ leaks out of cell resulting in cell death.
what is amphotericin B produced by
streptomyces nodosus
when is amphotericin B used
treatment of severe invasive fungal infection
widest spectrum of activity of all antifungals
rapid onset
resistance is rare
what are the pharmacokinetics of amphotericin B
metabolism poorly understood
poor PO absorption. Used IV - wide tissue distribution
little CSF penetration; intrathecal sometimes used
low TI
Nephrotoxicity - azotemia due to dose-dependent decrease in GFR
what are the AE of amphotericin B
infusion related reactions:
fever and rigors
decreased incidence following multiple doses
pre-medicate with Tylenol or Benadryl recommended
may treat rigors with low-dose meperidine
Nausea/vomiting, anemia, phlebitis
What is flucytosine
5-FC
synthetic pyrimidine analog (false nucleotide)
what is the MOA for Flucytosine
inhibits thymidylate synthase and incorporates into fungal RNA disrupting nucleic acid and protein synthesis
NOT used as monotherapy; resistance too high
what is the spectrim of activity for flucytosine
used in combo with ampotericin B (synergistic) for tx of systemic mycoses and meningitis caused by cryptococcus and candida spp.
used in combo with itraconazole for treatment of chromoblastomycosis infections
What needs to be monitored when using amphotericin B
K+, Mg++; replete aggressively in the presence of decreased GFR
What are the pharmacokinetics of Flucytosine
good PO absorption, penetrates CSF
dose adjustment required in renal impairment
what are the AE of flucytosine
reversible neutropenia, thrombocytopenia
dose-related bone marrow suppression
reversible hepatic dysfunction
more common: GI upset, N/V, diarrhea
What are the two groups of azoles
imidazole and triazoles
what are the imidazoles
ketoconazole
miconazole
clotrimazole
what are the traizoles
fluconazole
itraconazole
voriconazole
posaconazole
what is the MOA for the imidazole
inhibit C-14 alpha-demethylast (CYP450 enzyme), which block the demethylation on lanosterol to ergosterol thereby disrupting membrane structure
which of the imidazoles are too toxic for systemic use and are topical use only
miconazole and clotrimazole
what is ketoconazole
imidazole - may be used systemically (but systemic use replaced by newer triazoles)
what is the MOA for ketoconazole
inhibit C-14 alpha-demethylase - decrease syntehsis of ergosterol thereby disrupting membrane strucure
may be used sysetmically
should not be used with amphotericin B
what is the spectrim of activity of ketoconazole
candida, histoplasma, blastomyces, coccidioides but NOT aspergillus species
what are the pharmacokinetics of ketoconazole
topical and PO formation available
requires gastric acid for dissolution and absorption
does NOT penetrate CSF
endocrine effect: inhibit human gonadal and adrenal steroid homrone synthesis
what are the AE of ketoconazole
GI upset
hepatitis rare - d/c if raising LFTs
gynecomastia, decreased libido, menstrual irregulatiteis
drug interactions: CYP450 metabolized drugs
when is ketoconazole contraindicated
Pregnancy
What is the MOA for triazoles
inhibits synthesis of cellmembrane via fungal CYP 450 inhibition similar to ketoconazole, however, it does not interefere with the mammalian CYP 450 enzymes involvved in synthesis of other steroid hormones - no endocrine side effects
what is the spectrim of activity of fluconazole
candida, cyrptococcus neoformans, coccidiomycosis; no activity against aspergillus
what is the pharmacokinetics of Fluconazole
PO/IV, not dependent on gastic acid
Good CSF penetration
dose adjust in renal impairment
what are the AE of fluconazole
N/V/rashes, alopecia, hepatitis is rare
what are the contraindications for fluconzaole
teratogenic- should not be used in pregnancy
what is the spectrum of activity for itraconazole
broad: drug of choice for histoplasmosis, blastomycosis, sporotrichosis
what are the pharmacokinetics of itraconazole
good PO availability but requires gastic acid for absoprtion; no IV formulation
metabolized in liver
no dose-adjustment in renal impairment
dose not penetrate CSF well
what are the AE of itraconazole
N/V, rash, HA
HTN, Hypokalemia, edema
rarely hepatitis
chronic therpay can cause alopecia
potential drug-drug interactions: warfarin, statin, phenytoin
contra: teratogenic.
black box warning: CHF
what is the MOA for caspofungin
echinocandins
inhibits B (1,3) - D- Glucan synthase, an enzyme involved in fungal cell wall synthesis
what is the spectrum of activity for caspofungin
invasive aspergillus infection (2nd line agent)
- vericonazole 1st line agent
candidal infections:
-c. glabrata candidemia
zole-resistance candida esophagus
what is capsofungin not active against
zygomycytes and crypotococcus noeformans
what are the AE of echinocandins
generally well tolerated
histamine reaction with infusion - pretreat with benadryl
drug-drug interactions: cyclosporine, tacrolimus, rifampin
CNS penetration is poor
what is the MOA forNystatin
binds to ergosterol’ similar mechanisms of amphotericin B
too toxic for systemic use - never used IV
what is grieofluvin
Mechanism: inhibits mitosis
used for dermatophytic nail infections - accumulates in keratin-containing tissues
treatment may be required for 6-12 months
what are the drug to drug interactions with grieofulvin
induces CYP450 enzymes; increases rate of metabolism of other drugs including anticaogulants
avoid alcohol during therapy
what is terbinafine
mechanism: inhibits cell wall synthesis by inhibiting fungal squalene epoxidase - decreases the synthesis of ergosterol
where does terbinafine accumulate
skin, nails and fat - drug of choice for onychomycosis and dermatophytic infections
what are the SE/AE of terbinafine
contraindicated in nuring mothers - accumulates in breast milk
ARDs: hepatotoxicity - LFTs at baseline
What is coccidioimycosis
southwest US, aerosolized spores from soil
pulmonary disease
synovitis
hepatospenomegaly
meningitis leading to hydrocephalus
what are the treatment options for coccidioidomycosis
fluconazole or itraconazole, amphotericin B if severe/dissminated
what is Histoplasmosis
ohio, missouri, and mississippi river valeys
bird droppings in damp soil, bats
pulmonary disease to disseminated disease
disseminated form includes GI, cardiac, ocular and CNS effects
what is the treatment of choice for histoplasmosis
itraconazole
what is blastomycosis
great lakes region, inhalation of spores
pulmonary disease
skin lesions: sharply demarcated, grey to violet verrucal lesions, irregular borders
lytic bony lesions
prostatitis
what is the treatment of choice for blastomycosis
itraconazole
consider fungal infection in pneumonias not responding to antibiotics
what is Aspiergillosis
pulmonary disease most common
increased risk if have asthma or COPD
cavitary lesions
consider chronic form in patients whose respiratory symptoms do not respond to prolonged antibiotic therapy
what is the treatment options for aspergillosis
vericonazole, posaconazole (not first lien), capsofungin, amphotericin B
what is zygomycetes
rhizopus fungus, aggressive infections
nasopharynx of immunocompromised patients
what are the treatment options for zygomycetes
prompt surgical debridement
posaconazole, amphotericin B
what are antiprotozoal durgs
trimethoprim-sulfamethoxazole
metronidazole
what aare the antihelmintic drugs
albendazole
pyrantel pamoate
ivermectin
praziquantel
What is the MOA for metronidazole
activated by anaerobes to metabolites that damage DNA - the nitro group of metronidaazole serves as an electrol acceptor and forms toxic metabolite that disrupt DNA helical structure leading to cell death
what are the uses for metronidazole
amebiasis, giardiasis, tricomoniasis (and anaerobic bacterial infections)
what is considered a tissue agent and is co-administered with luminal agent, paromomycin
metronidazole
-asymptomatic patient may be treated with intraluminal agent alone
what are the pharmacokinetics of metronidazole
metabolized in liver- accumulates in aptients with severe hepatic disease; excreted in urine
What are the ARDs of metronidazole
GI disturbance (N/V), metallic taste, seizure, neuropathy, disulfiram (antabuse) effect with alcohol
what are contraindications for metronidazole
pregnancy, breast feeding, recent us of disulfiram
what are alternative therapies for metronidazole
tinidazole, ornidazole, and nitrazoxanide
What is the MOA for Bactrim
combination of TMP-SMX provides sequential, and thus synergistic blockade of FOLATE pathway: which leads to inhibition of thymidines synthesis
what is bactrim used for
cyclospora and isospora infections
what are the ARDS for bactrim
many potention
Rash, SJS, kernicterus, hemolysis in G6PD-deficiency patients; may lead to bone marrow suppression and anemia, renal impairement, hepatotoxicity
when should bactrim be avoided
patients with renal disease
drug-drug interactions with: warfarin, phenytoin, methotrexate
contra: newborns (<2months) and pregnancy
what is the primary treatment for nematodes (roundworms)
albendazole
what is the treatment for cestodes (tapeworms)
praziquantel
what is the treatment for trematodes (flukes)
praziquantel
what is the MOA for albendazole
binds to microtubules in the intesting and tegmental worm and larvae; impaired glucose uptake - glycogen depletion - degeneration of ER and mitochondria, release of lysosomes, and depletion of ATP/energy causing worm death
what are the uses for albendzaole
broadly effective against nematode infections (round worms)
what are the ARDS of albendazole
HA, elevated LFTs
rare: GI, alopecia
very rare: liver failure, myelosuppression, seizure
Contra: pregnancy
what is the moa pyrantel pamoate (OTC)
causes release of acetylcholine and inhibits cholinesterase; acts as a depolarizing neuromuscualr blocker, spastic PARALYSIS and release of helminths
what are the uses for pyrantel pamoate
NOT Preferred - new agents available
alternate to albendazole therapy for enterobius vermicularis (pin worms) infection
what are the ARDs with pyrantel pamoate
rare HA, dizziness, GI distress
what is the MAO for praziquantel
increases cell permeability to Ca2+ in schistosomes - strong contractions and paralysis of worm muscularture which leads to detachement and dislodgement and death
what are the uses of praziquantel
cestodes (tapeworms) and trematodes (flukes)
what are the ARDS of praziquantel
abdominal pain, dizziness, drowsiness
pts with cerebral cysticercosis experience CNS SE HA, seizures - from the death of parasites
CYP450
what is the MAO for ivermectin
binds and activates glutamate - gated chloride channels (GluCls) in invertebreate nerve and muscle cells; - hyperpolarization and death of helminth - does not cross BBB
what is the use of ivermectin
strongyloidiasis and onchocerviasis (“river blindness”); also used topically for head lice
what are the ARDS for ivermectan
neurotoxicity (CNS depression, ataxia) froma ctivation of GABA-nergic synapses; some cutanous effects
CI: prenancy, meningitis
