16/11/2019 Pharmacology of amphotericin B - UpToDate

Author: Richard H Drew, PharmD, MS, FCCP, FIDP

Section Editor: Carol A Kauffman, MD
Deputy Editor: Anna R Thorner, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2019. | This topic last updated: Sep 18, 2019.

INTRODUCTION

Amphotericin B is a polyene antifungal agent with activity in vitro against a wide variety of fungal
pathogens [1]. Amphotericin B exerts its antifungal effect by disruption of fungal cell wall
synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the
formation of pores that allow leakage of cellular components. This affinity may also account for
its toxic effects against select mammalian cells. Amphotericin B is generally considered cidal
against susceptible fungi at clinically relevant concentrations.

Despite the introduction of newer antifungal agents for the treatment of systemic mycoses,
amphotericin B remains the standard treatment for many severe, invasive fungal infections.
However, because of toxicities associated with its intravenous use, along with the expanded
availability of safer treatment options, it is frequently reserved for patients who have severe, life-
threatening invasive fungal infections or who are unable to tolerate alternative antifungal agents.

The pharmacology of amphotericin B will be reviewed here. The nephrotoxicity and the clinical
uses of amphotericin B (including the potential role as part of combination therapy) are
discussed in detail elsewhere. (See "Amphotericin B nephrotoxicity" and "Management of
candidemia and invasive candidiasis in adults" and "Chronic disseminated candidiasis
(hepatosplenic candidiasis)" and "Candida infections of the bladder and kidneys" and "Candida
osteoarticular infections" and "Treatment of endogenous endophthalmitis due to Candida
species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Candida
endocarditis and suppurative thrombophlebitis" and "Mucormycosis (zygomycosis)" and
"Treatment and prevention of invasive aspergillosis" and "Treatment and prevention of Fusarium
infection" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated
infection in HIV seronegative patients" and "Epidemiology, clinical manifestations, and diagnosis
of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Cryptococcus
neoformans infection outside the central nervous system" and "Treatment of blastomycosis" and
"Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of
disseminated histoplasmosis in HIV-uninfected patients" and "Diagnosis and treatment of
histoplasmosis in HIV-infected patients" and "Management of pulmonary sequelae and
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complications of coccidioidomycosis" and "Manifestations and treatment of nonmeningeal

extrathoracic coccidioidomycosis" and "Coccidioidomycosis in immunocompromised and
pregnant persons" and "Coccidioidal meningitis" and "Treatment of sporotrichosis".)

SPECTRUM OF ACTIVITY

Activity of amphotericin B has been demonstrated in vitro against a wide variety of clinical fungal
isolates, including most Candida spp, Aspergillus spp, the Mucorales, all of the endemic
mycoses, and most hyaline and brown-black molds. Activity has also been demonstrated against
Leishmania spp [2].

Other organisms that are usually resistant to amphotericin B include the organisms that cause
chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium spp, and some
Fusarium spp [2-6]. Amphotericin B demonstrates variable in vitro activity to clinical isolates of
Candida auris [7]. Approximately 10 to 15 percent were reported to be resistant [8,9]. The
potential role of amphotericin B in the treatment of C. auris is discussed in greater detail
separately. (See "Management of candidemia and invasive candidiasis in adults", section on 'C.
auris'.)

PHARMACODYNAMICS

Based on animal model data, amphotericin B exhibits concentration-dependent fungicidal

activity. A prolonged post-antifungal effect has been demonstrated against some Candida
species [10,11]. Neutropenic mouse models of both disseminated candidiasis and pulmonary
aspergillosis described correlations between peak concentration (Cmax) to minimum inhibitory
concentration (MIC) ratios and outcome [12-15].

AMPHOTERICIN B DEOXYCHOLATE

Pharmacokinetics — Despite over 40 years of clinical use, relatively little is known about the
pharmacokinetics of amphotericin B [16]. The pharmacokinetic profiles of the lipid-based
formulations of amphotericin B differ from those of amphotericin B deoxycholate and from each
other. (See 'Lipid-based amphotericin B formulations' below.)

Absorption — The drug is poorly absorbed (less than 5 percent) after oral administration. As
a result, treatment of invasive mycoses requires intravenous (IV) administration. An oral
suspension (no longer commercially available in the United States) is useful only in the treatment
of oropharyngeal candidiasis and is generally reserved for those infections that are refractory to
other agents. Systemic absorption following aerosol administration is also thought to be minimal.

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Distribution — Serum concentrations following IV infusions of 30 to 50 mg of amphotericin B

deoxycholate have ranged from 1 to 2 mcg/mL. The drug is highly protein bound (up to 95
percent), primarily to lipoproteins. It is extensively distributed throughout the body, with a volume
of distribution of approximately 4 L/kg.

Amphotericin B concentrations can be measured in various body tissues and fluids, including
liver, spleen, pleural fluid, peritoneal fluid, joint, vitreous body, and aqueous humor. Poor
penetration into inflamed and uninflamed meninges has been reported, despite demonstrated
clinical efficacy in central nervous system fungal infections, such as cryptococcal meningitis and
other fungal infections [2].

Metabolism/elimination — No metabolites have been identified. Drug elimination is

biphasic, with a terminal half-life of up to 15 days. Like volume of distribution, clearance
demonstrates a linear relationship to weight [17]. The primary route of elimination of
amphotericin B is not known; urine and biliary excretion account for less than 5 percent of the
administered dose. Serum levels are not influenced by hepatic or renal function or by
hemodialysis or peritoneal dialysis.

Dosing — Doses of IV amphotericin B deoxycholate range from 0.1 to 1.5 mg/kg per day. Doses
of 0.1 mg/kg per day of amphotericin B deoxycholate have been investigated as prophylaxis in
high-risk patients [18,19]. However, this practice has largely been replaced by alternative agents
with less toxicity. The usual dose for most invasive mycoses is 0.5 to 1 mg/kg per day. Doses
exceeding 1 mg/kg per day are generally reserved for treatment of mucormycosis and azole-
refractory invasive coccidioidomycosis (such as meningitis). Daily doses of 1.5 mg/kg per day
should not be exceeded. Pathogen- and disease-specific dosing recommendations have been
published by the Infectious Diseases Society of America (IDSA) for many invasive mycoses. The
IDSA clinical practice guidelines can be accessed at the IDSA's website [20]. The recommended
dosing of amphotericin B for each fungal disease and infection site is discussed in detail
separately. (See relevant topic reviews.)

The dose of amphotericin B does not need to be adjusted for renal dysfunction. In the setting of
renal dysfunction, alternate-day therapy of twice the daily dose has been described. However,
with the advent of lipid-based formulations, such a dosing strategy is rarely employed in current
practice.

The dosing of lipid-based formulations of amphotericin B is discussed below. (See 'Dosing'

below.)

Method of administration — Amphotericin B is most commonly administered intravenously, but

direct or local instillation of amphotericin B has been used in several clinical circumstances.

Intravenous — IV infusions are prepared by combining amphotericin B with 5 percent

dextrose in water (D5W) at a final concentration of 0.1 mg/mL. Although the incidence of acute
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hypersensitivity reactions from amphotericin B is rare, a test dose of 1 mg has been

recommended. The test dose can be given as an aliquot of the initial infusion, followed by the
remainder of the dose if there is no apparent reaction within 30 minutes. However, tolerance of
the test dose does not exclude other amphotericin B toxicities.

Infusion times are traditionally four to six hours. Amphotericin B has been given over shorter time
periods (eg, 45 to 60 minutes), but infusion-related reactions (such as fever) may be more
frequent, and this method is not recommended [21]. The practice of titrating the daily dose to the
target dose over several days has not been proven to lessen adverse reactions and may delay
optimal therapy.

IV administration of the total daily dose of amphotericin B given as a continuous infusion over 24
hours has been associated with less nephrotoxicity compared with administration over four hours
[22]. However, the efficacy of this administration schedule for patients with established infections
has not been proven. Furthermore, amphotericin B exhibits concentration-dependent
pharmacodynamics that may be compromised by continuous infusion. Continuous infusion of
amphotericin B is not US Food and Drug Administration approved and is not recommended.

Administration of premedications to patients receiving amphotericin B should be considered to

prevent infusion-related reactions and nephrotoxicity. (See 'Adverse effects' below.)

Bladder irrigation — Irrigation of the bladder with amphotericin B has been used in the
treatment of candiduria. There have been several nonblinded randomized trials comparing
amphotericin B bladder irrigation with oral fluconazole [23,24]. Although the use of amphotericin
B bladder irrigation resulted in clearing of candiduria in many patients, relapses were routinely
observed after several weeks. Traditionally, 50 mg of amphotericin B has been added to 1000
mL sterile water for irrigation and given as a continuous bladder irrigation daily for a period of
five days. However, this regimen requires the presence of an indwelling bladder catheter, which
itself is a risk factor for candiduria. Shorter treatment courses (one day) or reduced doses (as
low as 5 mg/day) have been recommended by some authors [25,26].

Current published guidelines on the treatment of candiduria do not recommend the routine use
of amphotericin B bladder irrigation, except in exceptional circumstances, such as treatment of
adult nonneutropenic patients with symptomatic cystitis due to fluconazole-resistant species
(Candida glabrata, Candida krusei) [27]. (See "Candida infections of the bladder and kidneys",
section on 'Fluconazole-resistant Candida'.)

Intraperitoneal — Local instillation of amphotericin B has also been reported in the treatment
of fungal peritonitis (alone or in combination with IV therapy). This practice is discouraged
because it causes abdominal pain and can contribute to adhesion formation and loss of the
peritoneum as a dialyzing membrane. Patients with fungal peritonitis should be treated with

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catheter removal and systemic antifungal therapy [27]. (See "Fungal peritonitis in peritoneal
dialysis", section on 'Treatment'.)

Intrathecal — Intrathecal administration of amphotericin B deoxycholate in the lumbar

subarachnoid space has been used primarily for the treatment of coccidioidal meningitis. Target
doses generally range from 0.1 to 1.5 mg at intervals ranging from daily to weekly [28]; lower
doses (ie, 0.01 mg) can be started and increased slowly until target doses are reached or the
patient shows signs of intolerance [29]. Adverse effects resulting from intrathecal administration
are frequent and include, but are not limited to, nausea and vomiting, headache, back and/or leg
pain, loss of bowel and/or bladder control, and nerve palsies. The development of arachnoiditis
is a serious complication of this form of therapy.

Intrathecal amphotericin B deoxycholate can also be given through a ventricular Ommaya or

Rickham reservoir. The target dose range is the same as for intrathecal administration in the
lumbar subarachnoid space (0.1 to 1.5 mg daily to weekly). Severe vomiting, headache, and
prostration can occur, and bacterial infection of the reservoir has been reported.

Cisternal administration of amphotericin B deoxycholate, either through a reservoir or by direct

injection, is used in some cases of coccidioidal meningitis in order to attain drug levels in the
basilar meninges, where the infection is localized [28]. The dose range is the same as for
intrathecal and intraventricular administration noted above. Severe headache, vomiting,
prostration, and even death have been reported following intracisternal injection of amphotericin
B [28,30]. Only experts at cisternal injections should undertake this form of therapy. (See
"Coccidioidal meningitis", section on 'Antifungal therapy'.)

Intravitreal — Intravitreal and intracameral (into the aqueous humor) injection of

amphotericin B has been used to treat fungal endophthalmitis. (See "Treatment of endogenous
endophthalmitis due to Candida species" and "Treatment of endophthalmitis due to molds".)

Aerosolized/nebulized — Administration of aerosolized (nebulized) amphotericin B (notably

amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B) has
been reported as a potential strategy in the prevention of invasive fungal infections in select
patient populations, such as patients with hematologic malignancies and lung transplant
recipients [12]. (See "Prophylaxis of invasive fungal infections in adults with hematologic
malignancies", section on 'Amphotericin B' and "Fungal infections following lung transplantation",
section on 'Nebulized amphotericin B'.)

Less frequently, aerosolized (nebulized) formulations of amphotericin B have been used as

adjunctive therapy (in combination with systemic antifungal therapy) in the treatment of invasive
fungal infections of the lung that are refractory to standard therapy or in patients intolerant of
standard therapy [13,31,32].

Adverse effects
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Infusion-related reactions — Infusion-related reactions, particularly nausea, vomiting, chills,

and rigors, are common with IV amphotericin B deoxycholate administration, usually occurring
either during infusion (within 15 minutes to 3 hours following initiation) or immediately following
administration of the dose. Treatment of amphotericin B-related nausea and vomiting (as well as
prevention of subsequent reactions) may require the use of a phenothiazine, such as
promethazine (usual adult dose 12.5 to 25 mg every four to six hours by mouth, intramuscularly
[IM], IV, or per rectum [PR]), prochlorperazine (usual adult dose 10 mg IM or IV or 25 mg PR
every four to six hours), or ondansetron.

Phlebitis is a complication that primarily occurs in patients receiving infusions via a small
peripheral vein. The addition of hydrocortisone (usual adult dose 25 mg) or heparin (usual final
concentration 500 to 1000 U/L) to the infusion may lessen infusion-related thrombophlebitis, but
trials to establish their efficacy are lacking and these adjuncts are not recommended [2].

Other ways to minimize amphotericin B-induced thrombophlebitis include:

● Infusion of the drug using a central line

● Use of alternating infusion sites
● Avoidance of final amphotericin B infusion concentrations exceeding 0.1 mg/mL
● Avoidance of infusion times of less than four hours

Drug-induced fever, chills, and headache can also be seen. These symptoms can be minimized
or prevented by premedication with acetaminophen (usual adult dose 650 to 1000 mg by mouth)
and/or diphenhydramine (usual adult dose 25 to 50 mg by mouth or IV). Nonsteroidal
antiinflammatory agents may also be useful in this setting. In a double-blind, placebo-controlled
trial, ibuprofen administered 30 minutes prior to amphotericin B deoxycholate reduced the rate of
occurrence of chills from 87 percent to 49 percent [33]. Meperidine (usual adult dose 25 to 50
mg IM or IV) may reduce amphotericin B-induced chills and rigors. However, meperidine is not
routinely recommended for premedication due to its potential side effects.

Nephrotoxicity — IV amphotericin B administration may result in nephrotoxicity. With

amphotericin B deoxycholate, a reversible and often transient decline in glomerular filtration rate
(GFR) has been described in 5 to 80 percent of patients. The net effect is an elevation (above
baseline) in the serum creatinine concentration. Severe renal failure due to amphotericin B
deoxycholate alone is less common, but the risks of such reactions increase with diuretic-
induced volume depletion or the concurrent administration of another nephrotoxin (such as an
aminoglycoside, cyclosporine, nephrotoxic cancer chemotherapy, or foscarnet). Amphotericin B
deoxycholate is substantially more nephrotoxic than the lipid-based formulations of amphotericin
B. This is discussed in greater detail separately. (See "Amphotericin B nephrotoxicity".)

Even though adequately controlled human clinical data to support such a practice is limited,
volume expansion with IV sodium chloride (a practice commonly known as "sodium loading")

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may ameliorate the decline in GFR. In the absence of contraindications, a total of 500 mL of 0.9
percent sodium chloride is typically given immediately prior to the amphotericin B infusion or
divided before and after amphotericin B administration. Such strategies, however, may not be
effective or practical in patients with critical illness with preexisting renal dysfunction [34]. (See
"Amphotericin B nephrotoxicity", section on 'Salt loading'.)

Electrolyte abnormalities — Hypokalemia, hypomagnesemia, and hyperchloremic acidosis

are reflections of an increase in distal tubular membrane permeability following IV administration
of amphotericin B. Many patients require significant amounts of potassium and/or magnesium
supplementation during therapy. Correction of hypokalemia may be difficult in patients with
persistent hypomagnesemia. (See "Clinical manifestations of magnesium depletion" and
"Amphotericin B nephrotoxicity", section on 'Electrolyte disorders'.)

Other reactions — A reversible, normochromic, normocytic anemia occurs in most patients

receiving IV amphotericin B, but the onset may be delayed for as long as 10 weeks after the
initiation of therapy [21]. Other hematologic side effects have also been described, including
severe leukopenia [35]. Transfusions are infrequently required. Elevations in liver function tests
have been associated with amphotericin B administration infrequently.

Severe allergic reactions (including anaphylaxis) are extremely rare but have been reported.

Patient monitoring — Patients receiving amphotericin B intravenously should be monitored

clinically for infusion-related reactions during and following each administration. Measurements
of renal function should be performed daily during initiation of therapy (up to two weeks) and at
least weekly thereafter, if stable. Some experts recommend that amphotericin B administration
be held or a lipid-based formulation substituted if the plasma creatinine concentration exceeds
2.5 mg/dL (265 micromol/L).

Serum electrolytes (particularly potassium and magnesium) should be assessed at baseline and
at least twice weekly throughout therapy. More frequent monitoring is recommended for patients
experiencing hypokalemia and hypomagnesemia as a result of amphotericin B administration.
Complete blood counts should be measured weekly throughout therapy. Monitoring of liver
function tests is usually not necessary unless the patient has clinical signs or symptoms
suggesting hepatic toxicity.

LIPID-BASED AMPHOTERICIN B FORMULATIONS

Lipid-based formulations of amphotericin B have been introduced in an attempt to reduce the

toxicities associated with amphotericin B deoxycholate [36,37]. Based on animal models and
clinical studies, these formulations reduce the risk of amphotericin B-related nephrotoxicity.
However, in a meta-analysis, the efficacy of amphotericin B deoxycholate and lipid-based

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formulations was similar [38]. The nephrotoxicity of amphotericin B is discussed in greater detail
separately. (See "Amphotericin B nephrotoxicity".)

The available lipid-based formulations are amphotericin B lipid complex (ABLC; Abelcet) and
liposomal amphotericin B (AmBisome) [39,40]. Amphotericin B cholesteryl sulfate complex
(amphotericin B colloidal dispersion, or ABCD; Amphotec) is no longer available in the United
States.

Safety and efficacy — Few randomized, comparative studies are available that directly
compare the safety and efficacy of these formulations to amphotericin B deoxycholate
intravenously. Controlled studies establishing the treatment efficacy of these agents are
somewhat limited and often involve patients previously treated with amphotericin B deoxycholate
[41].

● In a meta-analysis of randomized trials, the incidence of nephrotoxicity was significantly

lower with liposomal amphotericin B compared with amphotericin B deoxycholate (15 versus
33 percent) [42]. A lower incidence of nephrotoxicity was also observed with compounded
lipid emulsion/amphotericin B deoxycholate combination preparations compared with
amphotericin B deoxycholate (12 versus 31 percent), although we generally avoid such
preparations given incomplete and conflicting data regarding their safety, efficacy, and
stability. (See "Amphotericin B nephrotoxicity", section on 'Lipid-based formulations' and
'Amphotericin B plus fat emulsions' below.)

● A randomized trial compared ABCD with amphotericin B deoxycholate in 174 patients with
invasive aspergillosis [43]. Response rates were similar in both groups (52 and 51 percent,
respectively). ABCD was less likely to cause nephrotoxicity than amphotericin B
deoxycholate (25 versus 49 percent) but was associated with more infusion-related toxicity
(chills in 53 versus 30 percent).

● In a randomized trial comparing the efficacy of liposomal amphotericin B with amphotericin

B deoxycholate for the treatment of severe disseminated histoplasmosis in 81 AIDS
patients, the liposomal formulation resulted in a higher rate of clinical success (88 versus 64
percent) and lower mortality (2 versus 13 percent) [44].

● A trial comparing liposomal amphotericin B to amphotericin B deoxycholate for empiric

therapy in patients with persistent fever and neutropenia found no difference in composite
rates of successful treatment and patient outcomes [45]. However, significantly fewer
patients given liposomal amphotericin B had breakthrough fungal infections, infusion-related
fever, chills or rigors, or nephrotoxicity. This was the first trial to note a reduction in infusion-
related reactions associated with the liposomal formulation of amphotericin B.

● A study comparing ABLC (5 mg/kg per day) and liposomal amphotericin B (3 or 5 mg/kg per
day) as empiric therapy in patients with febrile neutropenia persisting after 72 hours of
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antibacterial treatment reported equivalent clinical outcome but reduced toxicity in the
liposomal amphotericin B group at both doses compared with ABLC [46]. Fever, chills and
rigors, nephrotoxicity, and toxicity-related discontinuation of therapy were all reduced in the
liposomal amphotericin B group, although all of the infusion reactions except chills and
rigors decreased after the first day in the ABLC-treated patients.

● Other open studies have reported successful use of these products in the treatment of
invasive candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, and leishmaniasis
[39,47].

● A randomized, double-blind trial in patients with invasive candidiasis compared liposomal

amphotericin B 3 mg/kg per day with micafungin and concluded that micafungin was as
effective and better tolerated [48].

Studies comparing lipid-based formulations for safety are sparse and are generally limited to
observational, uncontrolled trials. In one such study of patients with invasive coccidioidomycosis,
liposomal amphotericin B appeared to have less nephrotoxicity than ABLC [49].

Liposomal amphotericin B has a lower incidence of infusion-related reactions than amphotericin

B deoxycholate. However, a unique group of infusion reactions can occur with liposomal
amphotericin B, which have not been observed with amphotericin B lipid complex; a type 1
hypersensitivity reaction (labeled as complement activation-related pseudoallergy [CARPA]) is
thought to be a consequence of complement activation with resulting mast cell and basophil
secretory response [50,51]. Symptoms develop within five minutes and include chest pain,
dyspnea, hypoxia, abdominal pain, flushing, and urticaria and generally respond to stopping the
infusion as well as therapy with diphenhydramine [51,52].

Infusion-related intolerance to one formulation may not predict similar reactions to other
formulations. As an example, ABLC administration was uneventful in 34 of 40 patients (85
percent) who had previous severe reactions to liposomal amphotericin B in one retrospective
study [53]. Premedication with acetaminophen, hydrocortisone, and/or diphenhydramine was
used in many patients.

Electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and hyperchloremic acidosis,

may occur following the administration of both lipid-based and deoxycholate formulations of
amphotericin B (see 'Electrolyte abnormalities' above). False elevations of serum phosphate
may occur when samples from patients receiving AmBisome are analyzed using the PHOSm
assay used in Beckman Coulter analyzers, including the Synchron LX20 [54].

Pharmacokinetics — Lipid-based formulations of amphotericin B differ significantly in

pharmacokinetic profile from amphotericin B deoxycholate and from each other [36]. As an
example, ABLC appears to be taken up rapidly by the reticuloendothelial system and
demonstrates high tissue distribution, lower serum concentrations, and a prolonged elimination
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half-life when compared with liposomal amphotericin B. By contrast, liposomal amphotericin B

demonstrates a significantly lower volume of distribution, which results in high serum
concentrations, and a shorter elimination half-life than does ABLC or amphotericin B
deoxycholate [50,55]. Liposomal amphotericin B localizes in lung epithelial lining fluid, within liver
and splenic macrophages, and in kidney distal tubules.

Significant intra- and inter-subject variability in the pharmacokinetic profiles of lipid-based

formulations have also been reported in special populations, such as liposomal amphotericin B
pharmacokinetics in patients with critical illness [56].

Although lipid formulations of amphotericin B reach detectable concentrations in pleural fluid,

these concentrations are often below the minimum inhibitory concentration required for some
yeasts and dimorphic fungi [57].

Dosing — Doses of ABLC are generally 5 mg/kg per day. The dose of liposomal amphotericin B
ranges from 3 to 5 mg/kg per day (depending upon the indication). Studies of liposomal
amphotericin B in children indicate that comparable weight-based dosing can be used in this
population [58].

A randomized trial examining the impact of escalating the doses of liposomal amphotericin B to
10 mg/kg per day for the first two weeks of therapy in patients with invasive mold infections
(mostly invasive aspergillosis) demonstrated increases in treatment-related nephrotoxicity
without increased efficacy compared with standard dosing of 3 mg/kg per day [59]. For treatment
of cryptococcal meningitis, preliminary data suggest that liposomal amphotericin B at doses of
10 mg/kg per day were well-tolerated and may allow for less frequent dosing or shorter courses
of therapy [60]. Doses >10 mg/kg/day have exhibited dose-related, nonlinear, saturation-like
pharmacokinetics [61].

The recommended dosing of lipid-based formulations of amphotericin B for the treatment of each
fungal disease is discussed in detail separately. (See relevant topic reviews.)

Optimal doses and administration frequency for the prevention of invasive fungal infections are
uncertain. For example, once-weekly high-dose (ie, 10 mg/kg) liposomal amphotericin B has
been studied in the prevention of invasive fungal infections [62,63]. However, others have
reported an increase in the incidence of invasive fungal infections with such dosing [64].
Therefore, it should not be routinely used in such a manner.

Availability and cost — A report of the availability of amphotericin B deoxycholate worldwide

reported that the drug was not licensed or available in 22 of 155 (14.2 percent) and 42 of 155
(27.1 percent) of the countries surveyed, respectively [65]. In this report, the daily cost of
amphotericin B deoxycholate amphotericin B ranged from <$1 to $171 (USD).

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The drug acquisition cost of a lipid-based formulation of amphotericin B is significantly higher

than that of amphotericin B deoxycholate and may exceed $200 per day (depending upon the
formulation and contract pricing). Pharmacoeconomic analyses have been performed to assess
whether or not this increase in cost compared with amphotericin B deoxycholate can be offset by
reductions in toxicity and the costs associated with adverse reactions. In one such study, a
multicenter trial of 414 patients with febrile neutropenia showed that hospital costs were
significantly higher for the group receiving liposomal amphotericin B compared with amphotericin
B deoxycholate as first-line empiric therapy ($48,962 versus $43,184) based upon the cost of the
drug [66]. However, when the cost of the study drug was excluded, hospital costs were lower for
the liposomal amphotericin B group, which was probably due to the increased cost of the
management of the nephrotoxicity associated with amphotericin B deoxycholate. The authors
concluded that both drug cost and risks for nephrotoxicity impact the cost-effectiveness of
liposomal amphotericin B. Similar conclusions have been reached in analysis of amphotericin B
lipid complex in HIV-infected patients for the treatment of cryptococcal meningitis [67].

Amphotericin B plus fat emulsions — It has been suggested that mixing amphotericin B
deoxycholate with fat emulsions may reduce renal dysfunction [42] and infusion-related
reactions. However, incomplete and conflicting data exist regarding the safety, efficacy, and
stability of these mixtures [68]. Thus, their use should be considered investigational and is
discouraged.

DRUG INTERACTIONS

The following interactions are of particular concern with the use of amphotericin B:

● Amphotericin B should not be given concurrently or sequentially with other nephrotoxic

agents, if possible. (See "Amphotericin B nephrotoxicity".)

● Patients receiving digoxin or skeletal muscle relaxants may be predisposed to toxicity or

enhanced effect of these agents following amphotericin B-induced hypokalemia. (See
"Cardiac arrhythmias due to digoxin toxicity".)

● There are data linking amphotericin B and acute pulmonary reactions in patients receiving
concomitant leukocyte transfusions, but these reactions also can occur without
administering leukocyte transfusions. Infusions of amphotericin B should be separated as
far apart as possible from leukocyte transfusions whenever possible [2].

SUMMARY

● Amphotericin B is a polyene antifungal agent with activity in vitro against a wide variety of
fungal pathogens. Amphotericin B exerts its antifungal effect by disruption of fungal cell wall
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synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the
formation of pores that allow leakage of cellular components. Amphotericin B is generally
considered cidal against susceptible fungi at clinically relevant concentrations. (See
'Introduction' above.)

● Activity of amphotericin B has been demonstrated in vitro against a wide variety of clinical
fungal isolates, including Candida spp, Aspergillus spp, the Mucorales, all of the endemic
mycoses, and most hyaline and brown-black molds. Activity has also been demonstrated
against Leishmania spp. Organisms that are usually resistant to amphotericin B include the
organisms that cause chromoblastomycosis as well as Aspergillus terreus, Candida
lusitaniae, Scedosporium spp, and some Fusarium spp. (See 'Spectrum of activity' above.)

● Because of the toxicities associated with its intravenous use along with the expanded
availability of safer treatment options, amphotericin B is frequently reserved for patients who
have severe, life-threatening invasive fungal infections or who are unable to tolerate
alternative antifungal agents. (See 'Introduction' above.)

● Little is known about the pharmacokinetics of amphotericin B. The pharmacokinetic profiles

of the lipid formulations of amphotericin B differ from those of amphotericin B deoxycholate
and from each other. (See 'Pharmacokinetics' above.)

● The drug is poorly absorbed (less than 5 percent) after oral administration. As a result,
treatment of systemic mycoses requires intravenous administration. (See 'Absorption'
above.)

● Serum levels are not influenced by hepatic or renal function or by hemodialysis or peritoneal
dialysis. (See 'Metabolism/elimination' above.)

● Doses of intravenous amphotericin B deoxycholate range from 0.1 to 1.5 mg/kg per day.
The usual dose for most systemic mycoses is 0.5 to 1 mg/kg per day. (See 'Dosing' above.)

● Infusion-related reactions, particularly nausea and vomiting, are common with amphotericin
B deoxycholate administration. Drug-induced fever, chills, and headache can also be seen.
Medications can be given prior to amphotericin B administration to minimize or prevent
these adverse effects. (See 'Infusion-related reactions' above.)

● With amphotericin B deoxycholate, a reversible and often transient decline in glomerular

filtration rate (GFR) has been described. Volume expansion with intravenous sodium
chloride (a practice commonly known as "sodium loading") may ameliorate the decline in
GFR; 500 mL of 0.9 percent sodium chloride is typically given prior to the amphotericin B
infusion. (See 'Nephrotoxicity' above and "Amphotericin B nephrotoxicity".)

● Hypokalemia, hypomagnesemia, and hyperchloremic acidosis are reflections of an increase

in distal tubular membrane permeability. Many patients require potassium and/or
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magnesium supplementation during therapy. (See 'Electrolyte abnormalities' above.)

● Lipid-based formulations of amphotericin B have been introduced in an attempt to reduce

the toxicities associated with amphotericin B deoxycholate. The lipid formulations of
amphotericin B are substantially less nephrotoxic than amphotericin B deoxycholate. The
pharmacokinetics of these preparations differ significantly from amphotericin B deoxycholate
and each other. (See 'Lipid-based amphotericin B formulations' above and "Amphotericin B
nephrotoxicity", section on 'Lipid-based formulations'.)

● Doses of amphotericin B lipid complex are generally 5 mg/kg per day. The dose of liposomal
amphotericin B ranges from 3 to 5 mg/kg per day (depending upon the indication), whereas
amphotericin B cholesteryl sulfate complex is most commonly administered at doses
ranging from 3 to 4 mg/kg per day. (See 'Dosing' above.)

● The recommended dosing of the various formulations of amphotericin B for each fungal
disease is discussed in detail separately. (See 'Introduction' above.)

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