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3 Candidiasis Treatment: An Evolutionary Journey from Past to Present and…
Amphotericin B, despite its
effectiveness, must be injected
intravenously. Fluconazole can
Benet/harm
Morbidity linked with fungal
infections should be reduced if
fungal infections are treated
early
be used orally
Patients who are carefully
chosen may be treated to lessen
the likelihood of ascending and/
or hematogenously disseminated
illness
Inadequate therapy may promote
the growth of resistant organisms
Resistant organisms may be
selected in patients with
tracheobronchial colonization or
77
(continued)
oropharyngeal contamination of
respiratory secretions
Appropriate for those who have a fever despite receiving
407days of antibiotic medication
Amphotericin B deoxycholate (0.5–0.7mg/kg per day)
has typically been the recommended drug (A-II)
Amphotericin B deoxycholate (0.5–0.7mg/kg per day)
has typically been the recommended drug (A-II)
Voriconazole is not indicated for high-risk patients and
should only be used in people who have had an
Treatment options Recommendation
Itraconazole
Amphotericin B
Name
Antifungal
treatment of
neutropenic patients
with prolonged
fever in the absence
of antibacterial
therapy
Because of bladder irrigation, amphotericin B fails to
cure illness above the bladder level
The clinical relevance of candiduria can be difcult to
ascertain
Oral ucytosine (25mg/kg q.i.d.) may be useful in
treating candiduria caused by nonalbicans Candida
Fluconazole (6mg/kg per day) is generally used for
clinically stable patients (B-III)
Amphotericin B deoxycholate (0.6–0.7mg/kg per day)
or a lipid-associated formulation of amphotericin B
(3–5mg/kg per day) may be utilized in critically ill or
allogeneic bone marrow transplant or who have relapsed
leukemia
• Flucytosine in combination with
• Intravenous amphotericin B
• Intravenous or oral uconazole
Hepatosplenic
candidiasis (chronic
disseminated
refractory individuals
amphotericin or uconazole
candidiasis)
• Fluconazole (oral or intravenous)
• Amphotericin B (intravenous)
• Flucytosine (oral)
Candidiasis of the
urinary tract
species (C-III) in the absence of renal impairment
The majority of patients with primary Candida
pneumonia and laryngeal candidiasis have been treated
with amphotericin B (0.7–1.0mg/kg per day) (B-III)
Fluconazole is an effective treatment for milder cases of
candidal laryngitis (B-III)
• Intravenous amphotericin B
• Oral or intravenous uconazole
Candidiasis of the
lower respiratory
tract (pulmonary
and laryngeal
candidiasis)
78
Benet/harm
Because untreated illness has a
signicant morbidity, intensive
surgical and medicinal therapy is
essential. Candidal mediastinitis
can develop gradually
These infections are extremely
morbid and deadly, demanding
considerable medical and
surgical treatment
M. N. I. Bappy et al.
Because of the high morbidity
and mortality associated with
this infection, it necessitates
comprehensive treatment
Because of the devastating
implications of blindness,
considerable rehabilitation is
required
Infections of both natural and articial valves should be
treated surgically by replacing the damaged valve. The
most commonly used medical therapy has been
amphotericin B with or without ucytosine at maximal
tolerable doses (B-III)
In the event of spinal osteomyelitis, the optimal treatment
is a combination of surgical debridement of the aficted
area and antifungal therapy
Intravenous amphotericin B
Oral/ intravenous uconazole
Treatment options Recommendation
• Intravenous amphotericin B
• Oral/intravenous uconazole
Name
Arthritis and
Table 3.3 (continued)
candidal
(after open or arthroscopic
debridement or drainage)
osteomyelitis
(including
mediastinitis)
Oral ucytosine may be added to
Myocarditis,
pericarditis,
suppurative
After surgery, the overall period of therapy should be at
amphotericin B
phlebitis, and
candidal
endocarditis
least 6weeks, but perhaps much longer (CIII). Candida
endocarditis recurs frequently and necessitates at least a
year of attentive monitoring
Amphotericin B deoxycholate (0.7–1mg/kg per day)
combination with ucytosine (25mg/kg q.i.d.) is a
suitable initial therapy (B-III)
Flucytosine dosage should be adjusted to produce serum
levels of 40–60mg/mL
Patients with candidemia should have at least one dilated
retinal examination, preferably by an ophthalmologist
(A-II)
The bulk of clinical trials have used amphotericin B,
which is usually combined with ucytosine (B-III)
• Intravenous uconazole
• Flucytosine may be added to the
course of amphotericin B
Intravenous amphotericin B
Oral or intravenous uconazole
Flucytosine has been used in
combination with amphotericin B
Candidal
Meningitis candidal • Intravenous amphotericin B
endophthalmitis
3 Candidiasis Treatment: An Evolutionary Journey from Past to Present and…
Benet/harm
Chronic uconazole use has
been linked to increased vaginal
carriage of Candida nonalbicans
species in HIV-infected women,
although the relevance of this
observation is unknown
Immunocompromised hosts
require adequate nourishment
and water. Asymptomatic
oropharyngeal Candida species
colonization affects many
patients, and treatment seldom
results in microbiological cure
Multiple courses of medication
or the use of suppressive therapy
for recurrent infection are
signicant risk factors for
azole-resistant illness
Topical agents are usually
ineffective. Terbinane’s invitro
efcacy against Candida
onychomycosis is weak and
variable
–
79
uncontrolled diabetes), 2weeks of induction therapy with
a topical or oral azole should be followed by a 6-month
maintenance regimen
Fluconazole (150mg po once a week) and ketoconazole
(100mg once a day) are suitable maintenance regimens
Clotrimazole troches (one 10-mg troche ve times per
day) or nystatin (available as a suspension of 100,000U/
mL (dose, 4–6mL q.i.d.) or as avored 200,000U
pastilles (dosage, 1 or 2 pastilles 4–5 times per day for
7–14days) can be used to treat the rst episode of
oropharyngeal candidiasis
Topical uconazole (100mg/day for 7–14days) is as
Treatment options Recommendation
Name
Genital candidiasis Azoles Following management of the underlying cause (e.g.,
• Topical azoles (clotrimazole
troches)
• Oral azoles (uconazole,
ketoconazole, or itraconazole)
• Oral polyenes (such as nystatin or
oral amphotericin B)
Nongenital mucocutaneous candidiasis
Candidiasis of the
oropharynx and
esophagus
itraconazole (200mg b.i.d. for 1week, continued
effective as, and in some studies, even more successful
than, oral uconazole (100mg/day for 7–14days).
Fluconazole (A-I) has the same efcacy as itraconazole
solution (200mg/day for 7–14days). Ketoconazole and
itraconazole capsules are less effective than uconazole
due to variable absorption (A-I)
monthly for 3–4months)
Therapy with itraconazole The most effective treatment (A-II) appears to be
Candidal
onychomycosis
It is vital that the affected region remain dry
Drainage is the most signicant treatment for paronychia
Azole and polyenes
E.g., Nystatin, clotrimazole, and
miconazole
Topical nystatin and oral uconazole – –
Candidal skin
infections and
paronychia
Mammary
candidiasis
80
Advantages
Tetrazoles’ key advantage is their enhanced
specicity targeting fungal Cyp51, making this
class of medicines more tolerated
When compared to other echinocandins,
rezafungin exhibits superior pharmacokinetics.
Rezafungin has larger tissue distribution,
plasma exposure, and gut penetration than
other echinocandins, with less urinary
excretion. Rezafungin has the longest half-life
of any echinocandin (80h after a single dosage
and 150h after three doses), allowing for
once-weekly administration
Although oral cochleate administration and its
enhanced tolerability prole are promising,
similar efcacy to standard-of-care oral
therapies for mucosal candidiasis has yet to be
proven
M. N. I. Bappy et al.
In terms of oral delivery, penetration into
intraabdominal abscesses, and retention of
effectiveness against some echinocandin
resistant isolates, ibrexafungerp outperforms
echinocandins
Drugs Mode of action
Tetrazoles Tetrazoles, like azoles, inhibit Erg11p reversibly and
New members of existing
Table 3.4 Potential remedies that are underway
competitively, depleting ergosterol and compromising
membrane integrity in fungal membranes
Rezafungin (Cidara Therapeutics) is a new -1,3-glucan
synthase inhibitor with a substantially longer half-life than
anidulafungin, allowing for less frequent dosage
Rezafungin
(CD101)
classes
The amphotericin B formulation MAT2203, like other
amphotericin B formulations, sequesters sterols from
fungal membranes. Cochleate is absorbed through the
gastrointestinal tract. When the calcium levels in the
cochleate are low enough, the spiral unwinds and
distributes the drug directly onto fungal cells on contact,
boosting drug delivery while minimizing mammalian cell
toxicity
Ibrexafungerp (Scynexis) also targets -1,3-glucan synthase,
but it differs structurally from echinocandins and is the rst
member of a new class of antifungals known as
triterpenoids
Encochleated
Amphotericin
B (MAT2203)
(SCY-078)
Same target, new class Ibrexafungerp
3 Candidiasis Treatment: An Evolutionary Journey from Past to Present and…
Advantages
Fosmanogepix employs a new method of
action with a limited potential for cross-
resistance. It has a broad spectrum of activity,
has demonstrated efcacy in animal and
early-stage clinical trials, is orally accessible
and well tolerated, and shows promise in
infections caused by multidrug resistant
species such as C. auris
ATI-2307 has shown promise as a fungal-
selective drug, and invitro and invivo studies
suggest that it has the ability to treat a wide
range of Candida species, including highly
resistant isolates
Fungal-specic proteins BHBM, D0, and D13
have a new sphingolipid target. Although
contemporary hydrazycins lack a broad enough
range against clinically important Candida
species, the BHBM derivative D13 is a step
forward, and all congeners have been proven to
resensitize some azole-resistant species to
azoles
AR-12 has a broad antifungal range in yeasts
and molds and has been demonstrated in Phase
I human clinical studies to be well tolerated at
antifungal activity-relevant dosages
81
(continued)
The hydrazycins (E)-N′-(3-bromo-6-hydroxybenzylidene)-
2-methylbenzohydrazide (BHBM) and benzohydrazide
0.008–0.06g/ml), Candida glabrata (0.06–0.12g/ml), and
Candida auris (0.03g/ml)
Drugs Mode of action
Fosmanogepix Fosmanogepix inhibits Candida albicans (MIC90
Novel mechanism of
action
species, including azole and echinocandin-resistant strains,
as well as C. auris
ATI-2307 ATI-2307 is effective against a wide variety of Candida
(D0) were discovered during a search for chemicals that
Hydrazycins
(BHBM, D0,
D13)
specically inhibit the manufacture of fungal
glucosylceramide
anticancer characteristics, its antifungal activity is mediated
by two separate pathways. First, by suppressing fungal
acetyl CoA (Acs2p), which has a wide variety of
Repurposed AR-12 While kinase inhibition is responsible for AR-12’s
consequences due to the large range of processes in which
acetyl CoA is involved (e.g., carbon metabolism, histone
acetylation, ribosome function, and autophagy). When
Acs2p is suppressed, cell lysis eventually occurs. Second,
AR-12 enhances the host antifungal immune response by
down-regulating host chaperone proteins such as Grp89
and Hsp90; however, the exact details are unknown
82
Advantages
Calcineurin and Hsp90 are interesting targets
since they are involved in several fungal
growth and invasion processes, as well as
priming host cells to antifungal medicines and
antifungal immunity
MGCD290 is an oral drug with a unique target
that has showed promise invitro through its
effect on tolerance but has yet to be achieved
clinically. Because direct Hsp90
pharmacological suppression has
immunosuppressive consequences, blocking
Hsp90 by preventing its deacetylation may be
more appealing
M. N. I. Bappy et al.
AR-12 is fungicidal against Candida species (MIC 2–4g/
ml for Candida albicans, Candida glabrata, Candida
parapsilosis, Candida tropicalis, and Candida krusei) and
retains activity against strains with intermediate or resistant
uconazole MICs (MIC > 128g/ml) due to gain-of-
function mutations affecting efux pump activity
Drugs Mode of action
Calcineurin
and Hsp90
inhibitors
Combination/adjunctive
Table 3.4 (continued)
therapies
sodium butyrate cause apoptosis and cell cycle arrest
MGCD290 HDAC inhibitors such as trichostatin A, apicidin, and
3 Candidiasis Treatment: An Evolutionary Journey from Past to Present and…
83
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