ANTIFUNGAL AGENTS

AVRAMONI CRISTINA
 Antifungal therapy in the critical care setting is
primarily directed against Candida species, and this
is the focus of the folowing presentation
The most frequently encountered species in the
intensive care units are
Candida albicans
Candida glabrata
Candida parapsilosis
Candida tropicalis
Candida krusei
Systemic antifungal agents shown to be effective
for the treatment of invasive candidiasis comprise
4 major categories:
1. Polyenes (Amphotericin B ).

2. Triazoles (Fluconazole, Itraconazole,

Voriconazole, Posaconazole , Isavuconazole )
3. Echinocandins (Caspofungin, Anidulafungin,
and Micafungin).
4. Flucytosine
 Amphotericin B (AmB) is a naturally occurring
antibiotic that is fungicidal for most of the
pathogenic fungi in humans .
It is a potent antifungal agent in clinical use, but
also the most toxic antifungal agent, it is used mostly
as a backup agent.
It presents as:
Amphotericin B deoxycholate
Liposomal Amphotericin B
Amphotericin B lipid complex
Amphotericin B colloidal dispersion
 The adverse effects of AmB include an infusion-related
inflammatory response (fever, chills, nausea, vomiting,
rigors) and nephrotoxicity.
Nephrotoxicity :
 most common serious adverse effect associated with
AmB deoxycholate therapy,
 AKI in up to 50% of recipients and an electrolyte-
wasting tubular acidosis in a majority of patients.
 AmB deoxycholate–induced nephrotoxicity is
associated with a 6.6-fold increase in mortality.
Dosage : lipid formulation AmB 3–5 mg/kg daily
AmB is the treatment of choice for invasive candidiasis in
pregnant women .
 Each of the azoles has less activity against C. glabrata and
C. krusei than against other Candida species.
Fluconazole :
 greatest penetration into the CSF and vitreous, achieving
concentrations of >70% of those in serum , used in the
treatment of CNS and intraocular Candida infections.
 achieves urine concentrations that are 10–20 times the
concentrations in serum , preferred treatment option for
symptomatic cystitis .
Dosage for invasive candidiasis:
Loading dose: 800 mg (12 mg/kg daily),
Maintenance dose : 400 mg (6mg/kg daily) ; neonates
and children: 12mg/kg daily
 requires adjustment based on creatinine clearence.
 Voriconazole:
 effective in mucosal and invasive candidiasis
 used primarily for step-down oral therapy in patients
with infection due to C. krusei and fluconazole-
resistant, voriconazole-susceptible C. glabrata.
Loading doses :2X 6 mg/kg every 12 hours
Maintenance dosage: 3–4 mg/kg/ 12 hours
 because of the potential for cyclodextrin accumulation
and possible nephrotoxicity, intravenous voriconazole
is not recommended for patients with a creatinine cl.
<50 mL/minute.
 has not been studied systematically in fluconazole-
resistant Candida spp. and with the exception of C.
krusei, use is currently discouraged.
 caspofungin, anidulafungin, and micafungin
are available only as parenteral preparations .
 minimum inhibitory concentrations (MICs)
low for most Candida species, including C.
glabrata and C. krusei.
 each of these agents has efficacy in both
esophageal candidiasis and invasive
candidiasis.
 minimal adverse effects and achieve
therapeutic concentrations in all infection sites
with the exception of the eye, CNS, and urine.
 adjustment based on creatinine clearence not required.
 caspofungin is the only echinocandin for which dosage
reduction is recommended for patients with moderate
to severe hepatic dysfunction.
 caspofungin and micafungin are approved
for use in children .
Dosage in invasive candidiadis:
Caspofungin: loading dose 70 mg, then 50 mg daily;
pediatric dosage 50 mg/ m2 /day.
Anidulafungin: loading dose 200 mg, then 100 mg daily
Micafungin: 100 mg daily (no loading dose needed)
pediatric dosage: 2mg/kg/day.
 broad antifungal activity against most
Candida sp, with the exception of C. krusei.
 available as an oral formulation, with a short half
life (2.4–4.8 hours), excellent absorbtion.
 usually given in combination with another
antifungal agent due to a high rate of resistance
during monotherapy
 the most common use is in combination with AmB
for patients with more refractory infections, such
as Candida endocarditis, meningitis, or
endophthalmitis
 blood cultures
 antigen and antibody detection
 β-D-Glucan detection
 Polymerase Chain Reaction (PCR)
Nonneutropenic Patients:
 an echinocandin is recommended as initial therapy
(strong recommendation; high-quality evidence)
 fluconazole —acceptable alternative to an echinocandin as
initial therapy in selected patients, (not critically ill and
considered unlikely to have a fluconazole-resistant
Candida species , (strong recommendation; high-quality
evidence)
 transition to fluconazole (within 5–7 days) recommended
for clinically stable patients, isolates that are susceptible to
fluconazole (eg, C. albicans), and have negative repeat
blood cultures following initiation of antifungal therapy
(strong recommendation; moderate-quality evidence).
 testing for azole susceptibility is recommended
for all bloodstream infections, testing for
echinocandin susceptibility should be
considered in patients who have had prior
treatment with an echinocandin and among
those who have infection with C. glabrata or C.
parapsilosis (strong recommendation; low-quality
evidence).
 lipid formulation AmB - reasonable alternative for
intolerance, limited availability, or resistance to
other antifungal agents (strong recommendation;
high-quality evidence).
 for patients with suspected azole- and
echinocandin resistant Candida infections, lipid
form. AmB is recommended (strong
recommendation; low-quality evidence).
 Voriconazole is effective for candidemia, but
offers little advantage over fluconazole as initial
therapy (strong recommendation; moderate-quality
evidence).
 dilated ophthalmological examination, preferably
performed by an ophthalmologist, within the first
week after diagnosis (strong recommendation; low-quality
evidence).
 follow-up blood cultures performed at least every
other day to establish when candidemia has been
cleared (strong recommendation; low quality evidence).
 duration of therapy for candidemia without metastatic
complications is for 2 weeks after documented
clearance of Candida sp. from the bloodstream (strong
recommendation; moderate-quality evidence).
 CVCs should be removed as early as possible in the
course of candidemia when the source is presumed to
be the CVC and the catheter can be removed
safely(strong recommendation; moderate-quality evidence)
Empiric treatment in nonneutropenic patients :
 patients with risk factors ( broad spectrum
antibiotics, total parenteral nutrition, presence of
CVC, long stay in ICU, mechanical ventilation) for
invasive candidiasis and no other known cause of
fever, based on clinical assessment of risk factors
and surrogate markers (strong recommendation;
moderate-quality evidence)
 fluconazole is an alternative for patients who have
had no recent azole exposure and are not
colonized with azole-resistant Candida species
(strong recommendation; moderate-quality evidence)
 Neutropenic Patients:
 an echinocandin is recommended as initial
therapy (strong recommendation; moderate-quality evidence)
 lipid formulation AmB, is an effective but less attractive
alternative because of the potential for toxicity (strong recommendation;
moderate-quality evidence)
 minimum duration of therapy for candidemia without metastatic
complications is 2 weeks after documented clearance of Candida from
the bloodstream, provided neutropenia and symptoms attributable to
candidemia have resolved (strong recommendation; low-quality
evidence).
 in the neutropenic patient, sources of candidiasis other
than a CVC (eg, gastrointestinal tract) predominate, catheter
removal should be considered on an individual basis (strong
recommendation; low-quality evidence).
 Isolation of Candida Sp. from the respiratory tract:
 growth of Candida from respiratory secretions
usually indicates colonization and rarely
requires treatment with antifungal therapy
(strong recommendation; moderate-quality
evidence).
 Prophylaxis in the ICU Setting
 fluconazole could be used in high-risk patients
in adult ICUs with a high rate (>5%) of
invasive candidiasis (weak recommendation;
moderate-quality evidence).
 daily bathing of ICU patients with
chlorhexidine, which has been shown to
decrease the incidence of bloodstream
infections including candidemia, could be
considered (weak recommendation; moderate-
quality evidence)