Empiric antifungal therapy is rarely instituted except for febrile
neutropenic and other high-risk patients. Therapy generally is reserved
for situations in which yeast or mold is seen on KOH preparation
or when isolated organisms are thought to be pathogenic. Antifungal
standardized susceptibility testing is available for Candida spp,
and predict clinical outcome. In contrast, susceptibility testing for
most other fungi is not generally available; in vitro results for
these pathogens is less predictive of patient outcomes.
Amphotericin B in vitro inhibits several organisms producing
systemic mycotic disease in humans, including Aspergillus,
Histoplasma, Cryptococcus, Coccidioides, Candida, Blastomyces, Sporothrix, and
others. This drug can be used for treatment of these systemic fungal
infections. Pseudallescheria boydii and Fusarium are often resistant to amphotericin
Lipid-based Amphotericin B
The nephrotoxicity of amphotericin has resulted in the development of lipid-based amphotericin B products. The most commonly used agents are amphotericin B lipid complex (ABLC; Abelcet) and liposomal amphotericin B (L-AmB; AmBisome). Complexing amphotericin B with lipid allows larger doses to be administered (3–6 mg/kg, depending on the preparation and the fungal species). Liposomal amphotericin 10 mg/kg/d is no better than 3 mg/kg/d in the treatment of invasive mold infection; however, the larger dose is associated with significantly increased nephrotoxicity. The lipid formulations are particularly effective for treatment of visceral leishmaniasis. Short courses (5–10 days) with low doses (2–4 mg/kg/d depending on which preparation is used) are very effective in eradicating the parasite, probably because of distribution of the drug to the reticuloendothelial system, the major site of parasite invasion.
These preparations are associated with less nephrotoxicity than conventional amphotericin B. Liposomal amphotericin is somewhat less nephrotoxic than ABLC. Infusion-related adverse effects are variable, with liposomal amphotericin the best tolerated. Liposomal amphotericin is equal to or better than that of conventional amphotericin B in febrile neutropenia, particularly in prevention of emergent Candida infections.
Conventional Amphotericin B
The availability of lipid-based amphotericin, echinocandins, and triazoles has resulted in a greatly reduced role for conventional amphotericin for the prevention and treatment of fungal infection. If conventional amphotericin B is used, the daily dose for most fungal infections varies from 0.3 mg/kg to 0.7 mg/kg, though infections caused by Aspergillus and Mucor are often treated with 1–1.5 mg/kg daily.
Combined treatment with flucytosine is beneficial
in cryptococcal meningitis and possibly systemic candidiasis. In most patients with Foley catheter-related candiduria, antifungal therapy has no therapeutic benefit.
Neither kidney disease nor liver failure alters the pharmacokinetic
disposition of amphotericin. The drug concentrates in the lung,
liver, spleen, and kidney with minimal penetration into skin or
adipose tissue. The drug is not removed by hemodialysis.
The intravenous administration of amphotericin B often produces
chills, fever, vomiting, and headache. However, patients who experience infusion-related
adverse effects may benefit from slowing the rate of administration.
Tolerability may also be enhanced by temporary lowering of the dose or
premedication with acetaminophen and diphenhydramine. Addition of
25 mg of hydrocortisone to the infusion decreases the incidence
of rigors, and meperidine, 25–50 mg, is effective in arresting
rigors once they start. Electrolyte disturbances (hypokalemia,
hypomagnesemia, distal renal tubular acidosis) also commonly occur.
Kidney injury can be reduced with sodium supplementation. As a result,
administration of 0.5–1 L of 0.9% saline prior
to infusion of amphotericin B is recommended.
Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012 Jan;125(1 Suppl):S3–13.
Walsh TJ et al; Infectious Diseases Society of America. Treatment
of aspergillosis: clinical practice guidelines of the Infectious Diseases
Society of America. Clin Infect Dis. 2008 Feb 1;46(3):327–60.
Nystatin has a wide spectrum of antifungal activity but is used
almost exclusively to treat superficial candidal infections. It
is too toxic for systemic administration, and the drug is not absorbed
from mucous membranes or the gastrointestinal tract. Several preparations
are available, including oral suspension (100,000 units/mL)
and ointments, gels, and creams (100,000 units/g). For
oral candidiasis, 500,000 units of suspension is used as a “swish
and swallow” and repeated four times a day for at least
2 days after resolution of the infection. Infections of skin are treated
with cream or ointment, 100,000 units applied to the affected area
twice daily until resolution of the infection.
Flucytosine inhibits some strains of Candida, Cryptococcus, and other fungi. Dosages of 3–8 g
daily (75–150 mg/kg/d) orally produce
therapeutic levels in serum, urine, and cerebrospinal fluid. When
used as monotherapy, development of resistance is common; thus,
flucytosine is not used as a single drug therapy except in candiduria. In kidney disease, flucytosine may accumulate to toxic levels,
and dosage adjustment is needed. Because patients with HIV infection
and normal kidney function do not tolerate the previously used doses
of flucytosine (150 mg/kg/d in four divided doses),
75–100 mg/kg/d is recommended. The drug
is effectively removed by hemodialysis. Toxic effects include bone
marrow depression, abnormal liver function, and nausea. Bone marrow
suppression is caused by conversion of flucytosine to fluorouracil.
Combined use of flucytosine and amphotericin B in cryptococcal meningitis
and possibly systemic candidiasis has been shown to be of value.
Natamycin is a polyene antifungal drug effective against many
different fungi in vitro. When it is combined with appropriate surgical
measures, topical application of 5% ophthalmic suspension
may be beneficial in the treatment of keratitis caused by Fusarium, Acremonium (cephalosporium),
or other fungi. The toxicity after topical application
appears to be low.
Terbinafine, an allylamine, inhibits fungal cell membrane function
by blocking ergosterol synthesis. Terbinafine is available topically
as well as in 250-mg tablets for oral administration. The recommended dosage
is 250 mg daily for 12 weeks for toenail infections and 250 mg daily
for 6 weeks for fingernail infections (success rate about 70%).
Pulse therapy (1 week on and 3 weeks off) is as effective as continuous
therapy for 6–12 weeks. The drug also is active against
many strains of Candida and Aspergillus organisms and has been
used in combination with other antifungals to treat severe infections
with these pathogens. Most adverse effects are minor (diarrhea,
dyspepsia) or transient (taste disturbance). Rare cases of severe
hepatic injury have occurred.
Antifungal Imidazoles & Triazoles
These antifungal drugs inhibit synthesis of ergosterol, resulting in inhibition of membrane-associated enzyme activity, cell wall growth, and replication.
Clotrimazole, taken orally in the form of 10-mg troches five times daily, can prevent and treat oral candidiasis. Vaginal azole tablets inserted daily for 1–7 days are effective for vaginal candidiasis. Topical preparations for treatment of cutaneous dermatophytes are also available.
Fluconazole, a bis-triazole with activity similar
to that of ketoconazole, is water-soluble and can be given both orally
and intravenously. Absorption of the drug after oral administration
is not pH-dependent. It penetrates well into the cerebrospinal fluid
and eye. The drug has been shown to be effective primarily in the
treatment of Candida, Cryptococcus, and Blastomyces infections. Candida
albicans, C tropicalis, and C parapsilosus are
usually sensitive to fluconazole, but many other species of Candida (C krusei,
C glabrata, etc) are often resistant. Fluconazole-resistant
strains of C albicans primarily have been observed
in patients receiving antecedent fluconazole therapy. The drug is inactive against Aspergillus,
Mucor, and Pseudallescheria. Fluconazole
is effective in oropharyngeal candidiasis and candidal esophagitis. It is as effective or more effective
than vaginal creams and suppositories in vaginal candidiasis; a
single oral dose of fluconazole 150 mg is 80–90% effective.
Fluconazole, 400 mg intravenously and orally daily, is as effective
as amphotericin B, 0.5–0.6 mg/kg/d, for
candidemia in both neutropenic and nonneutropenic patients. Most
of these infections are intravenous line–related, and removal
of the line is critical to successful therapy. Fluconazole (200
mg/d) is effective as long-term suppressive therapy of
cryptococcal meningitis in patients with HIV/AIDS and is
the drug of choice in this setting. In the treatment of cryptococcal
meningitis, response rates and overall mortality rates are the same
in patients treated with oral fluconazole and with amphotericin
B. However, the mortality rate in the first 2 weeks is higher with
fluconazole and sterilization of cerebrospinal fluid is slower with
fluconazole. Consequently, induction generally takes place with amphotericin
B for 2 weeks, followed by oral fluconazole. A dosage of 400 mg
of fluconazole daily is effective therapy for coccidioidal meningitis
(80% response), but improvement is slow, taking as long
as 4–8 months. Increased doses (800–1200 mg/d)
have been used; however, they have not been found to be superior
to usual doses. Fluconazole, 400 mg daily, is effective prophylaxis against
superficial and invasive fungal infections in bone marrow and liver
transplant recipients, but concern has been raised about superinfection
with resistant organisms (C krusei, C glabrata). Because
the overall incidence of invasive fungal disease in HIV infection
is low, universal prophylaxis to prevent disease is discouraged,
especially with the advent of more potent antiretroviral therapy.
Fluconazole is also effective for the therapy of cutaneous leishmaniasis
due to Leishmania major in a dose of 200 mg/d
for 6 weeks.
Fluconazole is well absorbed after oral administration (> 90% bioavailability),
and serum levels approach those seen after administering the same
dose intravenously. Thus, unless the patient cannot take medication
by mouth or is hemodynamically unstable, the preferred route of administration
is by mouth. While generally well tolerated, fluconazole is associated
with dose-dependent nausea and vomiting. Altered liver function
tests (alanine aminotransferase [ALT], aspartate
aminotransferase [AST]) and hepatitis have been
reported. While less potent than other azoles (itraconazole, ketoconazole, posaconazole, voriconazole),
fluconazole inhibits cytochrome P450 resulting in reduced elimination
of certain agents. Rifampin and phenytoin increase metabolism of
fluconazole necessitating increased fluconazole dosage.
Itraconazole is an oral triazole with variable bioavailability.
It is moderately well absorbed from the gastrointestinal tract (food
increases absorption from 30% to 60%; antacids
and H2-receptor antagonists decrease absorption) and widely
distributed in tissues with the notable exception of the central
nervous system, where levels in spinal fluid are undetectable. Itraconazole
solution is more predictably absorbed than the tablets. While the
tablet formulation should be administered with food, the solution
is best absorbed on an empty stomach. The drug is metabolized by
the liver, and no dosage adjustment is needed in kidney disease.
Itraconazole is very active against most strains of Histoplasma
capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Sporotrichum
schenkii, and various dermatophytes. It is also active
against Aspergillus species but inactive against Fusarium and Zygomycetes. Itraconazole
in doses of 200–400 mg/d is effective and approved therapy
for localized or disseminated histoplasmosis. It is also effective
in sporotrichosis, dermatophytic infections (including those of
the nails), and oral and esophageal candidiasis. Itraconazole is
at least as effective as fluconazole in the treatment of nonmeningeal
coccidioidomycosis and may be superior in the management of skeletal
disease. At doses of 200 mg twice daily, itraconazole increases exercise
tolerance and decreases corticosteroid requirements in patients
with allergic bronchopulmonary aspergillosis. Itraconazole pulse therapy with 200 mg twice daily
for 1 week each month, repeated for 4 consecutive months, is effective
in the treatment of onychomycosis.
Adverse effects are similar to those of fluconazole, with anorexia, nausea, vomiting, and abdominal pain occurring most commonly. Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur uncommonly. Drugs that increase hepatic drug-metabolizing enzymes (isoniazid, rifampin, phenytoin, phenobarbital) may increase itraconazole metabolism, and increased doses may be needed when these drugs are administered concurrently with itraconazole. Itraconazole decreases the metabolism of cyclosporine, digoxin, and warfarin.
The usual dosage is 200 mg once or twice daily with meals.
Voriconazole is a triazole antifungal with broad
in vitro activity against most species of Candida and
molds, Aspergillus, Fusarium, Pseudallescheria, and
others. It is as efficacious as liposomal amphotericin in the therapy
of documented and suspected fungal infections in febrile neutropenic
patients, and it is superior to liposomal amphotericin in preventing
breakthrough fungemias in this patient population. Voriconazole is superior to conventional
amphotericin in the treatment of disseminated aspergillosis. Animal
data also suggest voriconazole to be the most effective agent against Aspergillus, particularly
in combination with caspofungin or another echinocandin. Voriconazole
is the drug of choice in the treatment of Fusarium and Scedosporium infections.
Voriconazole is widely used in the treatment of neutropenic patients
with suspected or documented fungal infection. Voriconazole has
limited activity against zygomycete pathogens, and some centers
have reported increased rates of infection due to Rhizopus and Mucor in stem
cell transplantation patients receiving voriconazole. Similar to
fluconazole, oral administration leads to predictable absorption.
The primary toxicity associated with voriconazole is infusion-related,
transient visual disturbances, particularly during the first week
of therapy. In addition, voriconazole is associated with photosensitivity reactions.
Similar to itraconazole, voriconazole is associated with hepatotoxicity
and numerous drug interactions. Enzyme inducers can decrease voriconazole
plasma levels with possible reduction in efficacy. Pharmacogenomic differences in cytochrome P450 2C19 can result in large differences in voriconazole clearance; therapeutic trough levels should be 1–5 mcg/mL. Voriconazole also is an inhibitor of cytochrome P450 activity reducing the clearance of numerous substrates, including cyclosporine and tacrolimus.
Posaconazole is an antifungal derivative of itraconazole with
similar spectrum of activity as voriconazole, including yeast and Aspergillus spp.
Unique from voriconazole, posaconazole has activity against the
zygomycete fungi approaching that of amphotericin. Salvage treatment
studies demonstrate efficacy in the treatment of these pathogens. Posaconazole
is superior to fluconazole as prophylaxis of neutropenia. The drug
is only available as an oral formulation, which may limit its use
in more acutely ill patients. Posaconazole should always be administered
with food to ensure adequate oral bioavailability; the drug is primarily eliminated
via nonrenal mechanisms. Similar to the other azole agents, posaconazole has
primarily upper gastrointestinal adverse events and occasional liver
function test abnormalities. While not as problematic as voriconazole,
posaconazole is an inhibitor of cytochrome P450.
Ketoconazole, the first orally
bioavailable azole, previously was used in the treatment of a variety
of fungal infections. However, the improved spectrum of activity,
reduced toxicity, and superior pharmacokinetics of newer azoles
have reduced ketoconazole to a secondary role.
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The echinocandins (anidulafungin, caspofungin, micafungin) act
by inhibiting fungal cell wall synthesis. They are active against Candida, including
nonalbicans species, as well as Aspergillus species.
They are not active against Cryptococcus or Fusarium. Their
long pharmacologic half-life confers the advantage of once-daily
dosing. No change in dose is necessary in patients with kidney disease;
however, moderate to severe hepatic disease necessitates a reduction
in dosage for caspofungin. Because dexamethasone, rifampin, and phenytoin significantly increase the metabolism of caspofungin, increased doses of the antifungal are necessary when these agents are given concomitantly.
Animal data suggest that caspofungin is inferior to voriconazole
in the treatment of Aspergillus; however, the addition
of caspofungin to voriconazole has been associated with in vitro
and in vivo additive or synergistic effects. Caspofungin is superior
to conventional amphotericin B in the treatment of candidemia, primarily
on the basis of greater patient tolerability. The echinocandins should
be considered the drugs of choice in the treatment of infections
due to C glabrata and C krusei. Micafungin has
been found to be as effective and less toxic than liposomal amphotericin
in the treatment of candidemia and invasive candidiasis. Anidulafungin
is at least as effective as fluconazole in the treatment of invasive
candidiasis. These agents are associated with minimal toxicity or adverse
effects. Histamine release is common with basic polypeptide compounds,
such as the echinocandins; thus infusion-related reactions have
been reported. While increased liver function tests have been observed
with the combination of caspofungin and cyclosporine, more recent analyses
suggest that these two agents can be safely administered together.
Considering the similarities in spectrum efficacy and safety between
products, the choice of echinocandin likely will be based on cost
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