CHAPTER 30 ANTIFUNGALS & ANTIVIRALS
● Dimorphic fungi: exist at lower temps
○ Histoplasma capsulatum
○ Blastomyces
○ Coccidioides
● Yeasts: form at higher temperatures
○ Candida species
■ Albicans is the most susceptible
■ Glabrata and krusei are harder to
treat due to resistance
○ Cryptococcus
● Molds: aspergillus and zygometes→ both require
special agents
● “Mold in the cold, yeast in the heat.”
● Zygomycetes includes Mucor species and Rhizopus
species
○ Invasive disease is called mucormycosis
Amphoteracin B
● Broad spectrum; binds to ergosterol altering cell
membrane permeability and causing cell death
○ Active against yeasts, molds, and
dimorphic fungi
○ Used as initial tx for invasive infections
such as cryptococcal meningitis,
histoplasmosis, and mucormycosis
○ Conventional: 0.1-1.5 mg/kg/day
○ Liposomal: 3-6 mg/kg/day
○ BBW: conventional should not exceed 1.5
mg/kg/day
■ Overdose= cardiopulmonary
arrest
○ SE: infusion related rxns, hypokalemia,
dec Mg, nephrotoxicity
○ Conventional requires premedication 30-
60 min before
■ APAP or NSAID
■ Diphenhydramine and/or HC
■ Meperidine to dec duration of
severe signs
■ NS boluses to dec risk of
nephrotoxicity
○ Lipid formulations have dec infusion rxns
and nephrotoxicity
○ Both formulations are yellow orange
○ Lipid based products are opaque
○ Additive inc risk with nephrotoxic agents
○ May inc risk of digoxin toxicity due to
hypokalemia
Flucytosine
● Works by penetrating fungal cells where it is
converted to fluorouracil which competes with
uracil, interfering with fungal RNA and protein
synthesis
● Recommended use with amphoteracin B for tx of
cryptococcal meningitis or Candida infections
● Covers yeasts including Candida and cryptococcus
● BBW: use with extreme caution in renal
dysfunction
● SE: myelosuppression, Inc SCr, Inc BUN, hepatitis
● Azoles: dec ergosterol synthesis and inhibit cell
membrane formation
○ CYP450 fungal inhibitors and interact with
CYP450 human enzymes too
○ All can cause LFT problems
○ Do not use fluc and vori in pregnancy
○ Fluc and vori penetrate the CNS→ good for
meningitis
● Posaconazole and isavuconazonium: active against
aspergillus and zygomycetes
○ Posa: tablet dose does not equal suspension
dose due to different bioavailability
Ketoconazole
● Tablet, cream, foam, gel, and shampoo
● 200-400 mg PO daily
● First azole, but due to toxicities→ mostly topical
● No renal dose adjustment
● BBW: hepatotoxicity
○ Concurrent use with cisapride, dofetilide,
pimozide, and quinidine is CI due to life
threatening ventricular arrhythmias and
TdP
● Use PO tablets only when you’re screwed with no
options
Fluconazole
● Reliable activity against candida albicans and
tropicalis, cryptococcus, and coccidioides
● Limited efficacy against glabrata due to resistance
● Krusei is fluconazole resistant
● 50-800 mg PO/IV daily
● Vaginal candidiasis: 150 mg PO x 1
● CrCL < 50 mL/min: dec dose by 50%
Itraconazole
● Covers albicans, tropicalis, dimorphic fungi, and
aspergillus
● Used less due to DDI, less data, $$$
● Primarily used for dimorphic fungi Blastomycosis
and histoplasmosis and nail bed infections
(onychomycosis)
● 200-400 mg PO BID
● Capsules and solutions are not interchangeable
● Solution to be taken without food while capsules
are taken with food
● CI: onychomycosis in patients with ventricular
dysfunction or history of HF
○ Coadministration with QT prolonging
drugs can inc plasma concentrations of
drugs and cause QT prolongation and
ventricular tachyarrhythmias and TdP
○ Do not give with nephrotoxic drugs
● SE: Inc LFTs, QT prolongation
● Strong 3A4 and Pgp inhibitor
Voriconazole
● Spectrum similar to itra, but better coverage of
Aspergillus, glabrata, and krusei
● No activity against Zygomycetes
● Drug of choice for Aspergillus
● Monitor for visual changes and phototoxicity
● Associated with CNS toxicities (HA, dizziness,
hallucinations, or ocular toxicity)
● Loading dose: 6 mg/kg IV Q12 x 2 doses
● Maintenance dose: 4 mg/kg IV Q12 or 200 mg PO
Q12→ used actual body weight for dosing
● Requires hepatic dose adjustment
● CrCL <50 mL/min: PO dosing preferred after initial
IV LD
○ The IV vehicle: SBECD can accumulate
and worsen renal function
● Trough levels: 1-5 mcg/mL
● Warnings: liver damage, visual disturbances (optic
neuritis and papilledema), embryo fetal toxicity,
QT prolongation (correct K, Ca, and Mg),
phototoxicity
● SE: visual changes, inc LFTs, Inc SCr, CNS toxicity
● Monitoring: LFTs, renal function, electrolytes,
visual function (for tx >28 days)
● Caution driving at night
● Avoid direct sunlight
● Hold tube feedings 1 hour before/after doses
● Suspension: shake for 10 sec before each use. Do
not refrigerate.
● First order, followed by zero order kinetics→
concentrations can inc dangerously when given
with 2C19, 2C9, and 3A4 inhibitors
● Avoid concurrent use with long acting
barbiturates. CBZ, EFZ (>400 mg/day), ergot
alkaloids, pimozide, quinidine, rifabutin, rifampin,
ritonavir (>800 mg/day), cobicistat, sirolimus, and
St John’s Wort
Posaconazole
● Spectrum similar to vori plus Zygomycetes
● Suspension: 200 mg PO TID of r400 mg PO BID
with a full meal (during or within 20 min of a
meal)
● Tablets: 300 mg PO BID on day 1, then 300 mg PO
daily with food
● IV: 300 mg BID x 1 day, then 300 mg daily
● CrCL <50 mL/min: PO dosing preferred because of
SBECD
● Warnings: QT prolongation→ correct K, Ca, and
Mg before tx
● Suspension and tablet are not interchangeable
● SE: inc LFTs, dec K, dec Mg
Isavuconazonium sulfate
● Prodrug of isavuconazole
● Similar spectrum to posa
● IV/PO: 372 mg Q8H for 6 doses, then 372 mg daily
● Caution in hepatic dysfunction
● CI: concurrent use with CYP3A4 inhibitors or
inducers and familial short QT syndrome
● Warnings: particulates→ requires a filter during
admin (0.2-1.2 micron)
● Avoid use with strong 3A4 inhibitors or inducers
● All azoles are 3A4 inhibitors
● Itra and keto: inc pH causes dec absorption
○ Antacids 2 hour before/after
 ○ PPIs and H2RAs need to be admin with reg ○ SE: HA, inc LFTs
cola ○ Strong 2D6 inhibitor and weak/moderate
● PPIs and cimetidine can dec absorption of posa 3A4 inducer
suspension and should be stopped during tx ● Clotrimazole: available in troche, topical and
● All azoles can inc INR in patients on warfarin→ vaginal forms
greatest with fluc, keto, and vori ○ Allow troche to dissolve slowly over 15-30
● Strong 3A4 inhibitors may inc concentrations of min
apixaban and rivaroxaban ○ SE: inc LFTs, N/V
● ECHINOCANDINS: inhibit synthesis of beta (1,3)-D- ○ Good for candida thrush
glucan, an essential component of the fungal cell ● Nystatin: suspension and tablet
wall ○ Use suspension QID and retain in mouth as
○ Effective against most Candida species long as possible before swallowing
including non-albicans that are resistant to ○ Minimal SE
azoles ○ Good for candida thrush
○ Activity includes Aspergillus but others are
generally preferred (combo better)
Pathogen First Line Tx
○ Well tolerate without any renal or hepatic
damage Candida albicans Thrush:
○ May cause histamine related rxns ● Mild: topicals→
○ SE: Inc LFTs, hypotension, dec K, dec Mg clotrimazole or nystatin
● If HIV + or
○ All are given once daily with no dose
moderate/severe:
adjustments needed fluconazole PO
● Caspofungin: 70 mg on day 1 then 50 mg IV daily Esophageal infection:
○ Moderate hepatic impairment: 70 mg on ● Fluconazole or
day 1, 35 mg IV daily after echinocandin
○ Inc dose to 70 mg IV daily when used with Bloodstream/invasive:
rifampin or other strong enzyme inducers ● If patient is neutropenic:
echinocandin (preferred),
● Micafungin: 100 mg IV daily (candidemia) and 150
fluconazole (alt)
mg IV daily (esophageal candidiasis) ● If neutropenic:
● Anidulafungin: 200 mg on day 1 then 100 mg IV echinocandin (preferred),
daily (candidemia) and 100 mg IV on day 1 then 50 amphoteracin B &
mg IV daily (esophageal candidiasis) fluconazole (alt)
● Griseofulvin: binds to the keratin precursor cells
Candida glabrata or Echinocandins or amphoteracin B
which prevents fungal invasion krusei
○ Indicated for dermatomycosis and tinea
infections of the skin, hair, and nails Aspergillus Voriconazole (preferred), liposomal
○ Narrow antifungal spectrum and less amphoteracin B, isavuconazonium
effective than other agents
Cryptococcus Induction in serious infections:
○ CI: pregnancy neoformans amphoteracin B + flucytosine
○ SE: photosensitivity Consolidation: fluconazole
○ Cross rxn possible with PCN allergy (prolonged)
○ Used for 2-4 weeks in tinea corporis and 4-8
Coccidioides Fluc, itra, or amphoteracin B
weeks in tinea pedis
○ May lead to OC failure Histoplasma Liposomal amphoteracin B
● Terbinafine: inhibits squalene epoxidase leading to capsulatum following by itra
cell death
Zygomycetes Amphoteracin B + posa, or isa
○ Available PO, oral granule, and topical
○ CI: active liver disease Dermatophytes Nail bed infections: itra,
○ Can exacerbate lupus
 ○ Acyclovir is cheapest but dosed 5 times a
terbinafine, or fluc (confirm fungal
before tx) day
○ Valtrex is the prodrug→ dosed less
frequently
● Common SE include HA, N, and abdominal pain
○ If a virus is resistant to acyclovir, it will be
● Liquid suspensions should not be refrigerated
resistant to Valtrex and famciclovir
VIRAL INFECTIONS:
○ Acyclovir resistant lesions are tx with
● INFLUENZA:
Foscarnet
○ Neuraminidase inhibitors: inhibit the
○ Suppressive tx will reduce frequency
enzyme that enables the release of new
● HSV encephalitis: IV acyclovir 10 mg/kg/dose Q8H x
viral particles from infected cells
14-21 days
■ Decrease sx by one day
● HSV esophagitis and pneumonitis: 5 mg/kg/dose
■ Beneficial if started 48 hours after
Q8H
infection
● Herpes Labialis:
○ Oseltamivir: 75 mg PO BID for 5 days
● Docosanol: (Abreva) Apply 5x daily at the first sign
■ Ppx: 75 mg daily x 10 days
of outbreak. Continue until healed.
■ Requires renal dose adjustment
● Acyclovir topical cream: Apply 5x a day for 4 days
with CrCL <60 mL/min
(can be used on genital sores)
■ SE: HA, N/V/D, abdominal pain
● Acyclovir buccal tablet: Apply 50 mg tablet as a
■ Risk that it will dec influenza
single dose in upper gum region
vaccine effectiveness if given within
● Penciclovir topical cream: apply every 2 hours
2 weejs
during waking hours for 4 days
○ Zanamivir: 10 mg BID inhaled x 5 days
● Shingles/Herpes Zoster: usually occurs in >60 YO
■ Ppx: 10 mg once daily for 10 days
○ Unilateral rash
(household setting) or 28 days
○ ARV most effective when started within 72
(community outbreak)
hours
■ May cause bronchospasm→ do not
○ Pain can be tx with: Lidoderm patch, gel or
use in asthma/COPD with any
with PN agents such as anticonvulsants and
breathing problems
antidepressants , sometimes NSAIDs and
○ Peramivir: 600 mg IV as a single dose
opioids
■ Adjust in CrCL <50 mL/min
○ Acyclovir 800 mg PO x5 daily for 7-10 days
● HERPES VIRUS: HSV-1 and 2, varicella zoster virus,
○ Famciclovir 500 mg PO TID for 7 days
CMV, EBV, Kaposi sarcoma associated herpes (HHV-
○ Valtrex 1 g PO TID for 7 days
8, HHV-6, and HHV-7
● CMV: causes retinitis, colitis, and esophagitis
○ Acyclovir, Valacyclovir, and Famciclovir
○ Ganciclovir and valganciclovir are ToC
○ Caution in elderly, renal impairment,
○ Foscarnet and cidofovir are reserved for
nephrotoxic agents
refractory cases
○ Infuse acyclovir at least 1 hour and remain
○ Secondary ppx is needed in patients with
hydrated
HIV with CMV retinitis and CD4 counts
○ SE: malaise, HA, N/V/D, inc SCr with crystal
<50→ valgan preferred
nephropathy (IV acyclovir)
● CMV Preferred Tx:
○ Acyclovir dose based on IBW in obese
○ BBW: myelosuppression
patients
○ SE: thrombocytopenia, neutropenia,
○ 5 mg/kg IV acyclovir = 1000 mg PO valtrex
leukopenia, and anemia
● Genital herpes: patients experience a prodromal
○ Patients with reproductive potential should
phase of mild tingling or shooting pain in legs, hips,
use contraception during tx and 30 days
thighs or buttocks before lesions appear
after
○ Tx must be initiated within 1 day or lesion
○ IV gan 5 mg/kg= 900 mg valgan PO
onset
 ○ Ganciclovir: prepare in sterile water→ not
bacteriostatic
■ Tx: 5 mg/kg IV BID then 5 mg/kg IV
daily
○ Valganciclovir: Prodrug of gan with good
bioavailability
■ Tx: 900 mg PO BID x 21 days
■ Dec dose and extend interval in
CrCL <60 mL/min
■ Refrigerate suspension and discard
after 49 days
● Cidofovir: HIV pts only
○ 5 mg/kg/week IV x 2 weeks then 5 mg/kg
once every 2 weeks
○ Dec dose or discontinue based on CrCL
○ BBW: nephrotoxicity
○ CI: SCr >1.5 mg/dL, CrCL <55 mL/min
○ Patients should be hydrated before each
dose
○ Can dec TDF clearance
● Foscarnet: BBW: renal impairment, seizures due to
electrolyte imbalances
○ SE: inc SCr
○ Vesicant
● EBV: usually resolves within 2-4 weeks with no drug
tx or vaccine