Pharmacology of amphotericin B

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. With the exception of neonatal candidiasis and treatment of Candida urinary tract infections, lipid-based formulations (most notably liposomal amphotericin B) have largely replaced amphotericin B deoxycholate due to their improved tolerability [2,3].

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 and chorioretinitis 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 patients without HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" 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 patients without HIV" and "Treatment of histoplasmosis in patients with HIV" and "Management of pulmonary sequelae and complications of coccidioidomycosis" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients" 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 [4], all of the endemic mycoses, and most hyaline and brown-black molds. Activity has also been demonstrated against Leishmania spp [5].

Fungal pathogens that are usually resistant to amphotericin B include the organisms that cause chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium spp, and some Fusarium spp [5-9].

Candida auris is an emerging fungal pathogen considered to be a serious global threat [10]. There are no Clinical and Laboratory Standards Institute (CLSI) amphotericin B interpretive breakpoints available for C. auris. Therefore, tentative susceptibility testing breakpoints are based on other Candida species. The US Centers for Disease Control and Prevention (CDC) currently utilize a tentative breakpoint of >2 mcg/mL (or an Etest^® result of 1.5 mcg/mL) as resistant [11]. Based on these criteria, about 30 percent have been resistant to amphotericin B [11]. The potential role of amphotericin B (alone or as part of combination therapy) [12,13] in the treatment of C. auris is discussed in greater detail separately. (See "Management of candidemia and invasive candidiasis in adults".)

PHARMACODYNAMICS — Based primarily on data from murine disseminated candidiasis models, amphotericin B is thought to exhibit concentration-dependent fungicidal activity. A prolonged post-antifungal effect has been demonstrated against some Candida species [14,15]. Neutropenic mouse models of both disseminated candidiasis and pulmonary aspergillosis described correlations between peak concentration (C_max) to minimum inhibitory concentration (MIC) ratios and outcome [16-19].

AMPHOTERICIN B DEOXYCHOLATE

Pharmacokinetics — Despite several decades of clinical use, relatively little is known about the pharmacokinetics of amphotericin B [20]. 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.

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 [5].

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 [21]. 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 concentrations are not influenced by hepatic or renal function or by hemodialysis or peritoneal dialysis.

Dosing — Treatment doses of IV amphotericin B deoxycholate range from 0.5 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 [22,23]. However, this practice has largely been replaced by alternative agents with less toxicity.

The usual dose of IV amphotericin B deoxycholate 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 [24]. 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 deoxycholate does not need to be adjusted for renal dysfunction. In the setting of renal dysfunction, alternate-day therapy of twice the daily dose has historically been described. However, with the advent of lipid-based formulations, such a dosing strategy is rarely employed in current practice. No dosage adjustment or supplemental dose is recommended in patients receiving concomitant renal replacement therapy.

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

Method of administration — Amphotericin B deoxycholate is most commonly administered intravenously, but direct or local instillation has been used in several clinical circumstances [25].

Intravenous — IV infusions are prepared by combining amphotericin B deoxycholate with 5% dextrose in water (D5W) at a final concentration of 0.1 mg/mL. Although the incidence of acute 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 [26]. 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 deoxycholate given as a continuous infusion over 24 hours (when combined with therapeutic drug monitoring) has been associated with less nephrotoxicity compared with administration over four hours [27,28]. However, the efficacy of this administration schedule for patients with established infections has not been proven in controlled clinical trials. 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 (FDA) approved and is not currently 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 deoxycholate has been used in the treatment of candiduria. There have been several nonblinded randomized trials comparing amphotericin B bladder irrigation with oral fluconazole [29,30]. 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 [31,32].

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) [2]. (See "Candida infections of the bladder and kidneys", section on 'Fluconazole-resistant Candida'.)

Intraperitoneal — Local instillation of amphotericin B deoxycholate 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 catheter removal and systemic antifungal therapy [2]. (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 [33]; lower doses (ie, 0.01 mg) can be started and increased slowly until target doses are reached or the patient shows signs of intolerance [34]. 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 [33]. 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 [33,35]. 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 and chorioretinitis 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 [16]. It has also been used for secondary prophylaxis in patients with allergic bronchopulmonary aspergillosis (ABPA) [36]. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Amphotericin B' and "Fungal infections following lung transplantation", section on 'Prophylaxis'.)

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 [17,37,38].

Antibiotic lock — Antibiotic lock therapy for catheter-related bloodstream infections (CRBSIs) refers to the instillation of a highly concentrated antibiotic solution (with or without heparin) into the intravascular catheter, which is allowed to dwell within the catheter while not in use and is then removed prior to catheter use. (See "Lock therapy for treatment and prevention of intravascular non-hemodialysis catheter-related infection".)

In general, management of CRBSIs due to fungi consists of catheter removal and systemic antifungal therapy. However, use of amphotericin B deoxycholate as an antibiotic lock solution in intravenous and peritoneal dialysis catheters for line salvage as an option to catheter removal has been described. Concentrations of amphotericin B deoxycholate reported range from 0.33 to 2.5 mg/mL, most commonly 2.5 mg/mL [39-46]. In such settings, amphotericin B should be diluted with D5W, not normal saline. Dwell times are usually about 8 hours and should not exceed 12 hours. Limited experience with liposomal amphotericin B in this setting at a concentration of 2 mg/mL (allowed to dwell for 8 to 12 hours daily and then withdrawn) has also been published [47-49].

Antibiotic lock therapy is strongly discouraged for tunneled hemodialysis catheters that are colonized/infected with fungi, and in nearly all cases, the infected catheter should be removed. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention".)

Adverse effects

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 (eg, promethazine, prochlorperazine,) 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 [5].

Other ways to minimize 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 and/or diphenhydramine, Nonsteroidal anti-inflammatory 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 [50]. Meperidine may reduce amphotericin B-induced chills and rigors. However, meperidine is not routinely recommended for premedication due to its potential side effects.

Nephrotoxicity — IV administration of any formulation of amphotericin B 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 (depending largely on the patient population, definition of nephrotoxicity, and the formulation utilized). 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") 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 [51]. (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 and early and aggressive electrolyte repletion is often required. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion" and "Amphotericin B nephrotoxicity", section on 'Electrolyte and acid-base 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 [26]. Other hematologic side effects have also been described, including severe leukopenia [52]. 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.

Increasing attention has been made to the monitoring of antifungal serum concentrations (more commonly known as therapeutic drug monitoring [TDM]) [53]. However, in contrast to many of the azole antifungals (most notably voriconazole), established serum concentration targets are presently lacking for amphotericin to optimize efficacy while minimizing toxicity, and serum amphotericin B levels are unavailable to most clinicians.

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 [54,55]. Based on animal models and clinical studies, these formulations reduce the risk of amphotericin B-related nephrotoxicity. In a meta-analysis, the efficacy of amphotericin B deoxycholate and lipid-based formulations was similar [56]. 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) [57,58]. Due largely to their improved safety (most notably decreased nephrotoxicity), the lipid-based formulations have replaced amphotericin B deoxycholate in many invasive fungal infection treatment guidelines.

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 [59].

●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) [60].

●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) [61].

●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 [62]. 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 antibacterial treatment reported equivalent clinical outcome but reduced toxicity in the liposomal amphotericin B group at both doses compared with ABLC [63]. 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.

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 [64].

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 [65-67]. 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 [66,68].

Infusion-related intolerance to one formulation may not predict similar reactions to other formulations [63,69]. 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 [69]. 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 [70]. Assessments of C-reactive protein may also be impacted by lipid-based formulations of amphotericin B; notably liposomal amphotericin B can produce false declines in serum/plasma CRP concentration [71].

Pharmacokinetics — Lipid-based formulations of amphotericin B differ significantly in pharmacokinetic profile from amphotericin B deoxycholate and from each other [54,72]. 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 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 [65,72]. Studies in morbidly obese patients demonstrate limited distribution into adipose tissue [73]. 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 [74,75].

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 [76].

The impact of dose escalation on the pharmacokinetics of liposomal amphotericin B (>10mg/kg/day) has been investigated. In prior reports, doses of LAmB exceeding 10mg/kg/day demonstrated nonlinear (saturable) pharmacokinetics [77,78]. More recently, a variety of doses of liposomal amphotericin B were studied in adult patients with HIV and cryptococcal meningitis, and [79].no evidence of nonlinear kinetics at this dose and frequency were observed.

Dosing — Lipid formulations of amphotericin B are generally administered in hospital settings and standard doses are used. In rare selected circumstances (eg, outpatient treatment), higher doses and/or extended interval dosing can be used. When alternative dosing regimens are used, an expert in the treatment of fungal infections should be consulted.

Standard dosing

●Typical adult dosing − Doses of ABLC are generally 5 mg/kg per day. The dose of liposomal amphotericin B usually ranges from 3 to 5 mg/kg per day (depending upon the indication). Dosing for specific indications is discussed in specific UpToDate topics and in Lexicomp drug monographs.

●Pediatric dosing − Studies of liposomal amphotericin B in children indicate that comparable weight-based dosing can be used in this population [77].

●Hepatic and renal dysfunction − No dosing adjustment is recommended for liposomal amphotericin B in the setting of either hepatic or renal insufficiency.

●Renal replacement therapy − No dosing adjustment is recommended in the setting of renal replacement therapy.

●Extracorporeal membrane oxygenation (ECMO) − Because liposomal amphotericin B is highly lipophilic and highly protein bound, sequestration of drug within the ECMO circuit is possible. However, data in this population are generally limited to case reports [80,81]. One such report describes an adult with blastomycoses treated with L-AMB (5 mg/kg/day) who was initiated on ECMO and concurrent continuous renal replacement therapy (CRRT) [80]. Serum concentrations were obtained after a dose increase to 10mg/kg/day. When compared to external data in non-ECMO patients at a similar dose, the investigators reported an approximate 50 percent decrease in observed peak concentration (Cmax), a more than doubled volume of distribution (Vd) and slightly increased drug clearance.

●Obesity − Optimal dosing of lipid-based formulations of amphotericin B in morbidly obese patients is unknown. In one trial examining doses of 1 mg/kg and 2 mg/kg of liposomal amphotericin B in 16 individuals with a body mass index >40 kg/m², the drug’s clearance was independent of weight [73]. Investigators proposed that a maximum dosing weight of 100 kg be used in patients ≥100 kg and would therefore receive a fixed dose of either 300 or 500 mg (corresponding to weight-based dosing of 3 and 5 mg/kg, respectively). However, results of such studies are impacted by the formulation studied, limited sample population, and the complex nature of drug release from the liposomes, among other factors [82].

In patients receiving liposomal amphotericin B whose total body weight (TBW) exceeds 120 percent of their ideal body weight (IBW), receipt of 5mg/kg based on TBW (when compared to use of adjusted body weight [adjBW]) experienced higher rates of nephrotoxicity (57 versus 35 percent, respectively [P value of 0.016]) and early discontinuation of LAmB due to toxicity (33 versus 17 percent [P = 0.030]) [83]. However, given a trend toward increased 90-day mortality in the adjBW group relative to the TBW group (60 versus 45 percent respectively, [P = 0.079]), the higher doses resulting from TBW-based dosing are likely justified in those critically ill with severe, potentially life-threatening infection.

●Pregnancy – the optimal dosing weight (IBW versus actual body weight versus adjBW) in pregnant women is not addressed in present treatment guidelines. In one case report, IBW was utilized for the treatment of mucocutaneous leishmaniasis [84].

Alternative strategies — In rare selected circumstances, higher doses and/or extended interval dosing can be used. When designing an alternative dosing regimen, an expert in the treatment of fungal infections should be consulted.

●Transition to outpatient therapy − Extended-interval dosing has been reported to be effective for patients who have a documented response to initial daily therapy in hospital and who require continued treatment as an outpatient [46]. Due primarily to it long half-life, the dosing interval for liposomal amphotericin B can be extended to three times weekly (ie, 5 mg/kg three times weekly) [85]. However, the majority of reports utilizing liposomal amphotericin B are for prevention of invasive fungal infection (see below).

●Prophylaxis (when other agents cannot be used) − Use of intravenous liposomal formulations of amphotericin B (most notably liposomal amphotericin B) for prevention of invasive fungal infections is generally restricted to situations in which azole-based strategies are limited by drug interactions (most notably vincristine, cyclosporine, and/or tacrolimus) or toxicity [86].

The optimal dosing regimen is not known. Lower doses of liposomal amphotericin B (2 to 5 mg/kg) and extended dosing intervals (most commonly 2 to 3 times weekly) have been reported to reduce fungal colonization but not invasive fungal infections in patients with hematologic malignancies undergoing chemotherapy or bone marrow transplantation [87]. Weekly high-dose (ie, 10 mg/kg) liposomal amphotericin B has been reported to be safe and effective for the prevention of invasive fungal infections in some studies, but others have reported toxicity and/or increases in invasive fungal infections with such regimens [88-93]. Thus, weekly high-dose therapy is not recommended. Because the balance between efficacy and toxicity is delicate, a specialist should be consulted when designing a prophylactic regimen.

●Other alternative regimens − 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 dosing of 3 mg/kg per day [94].

The need for dose escalations (up to 10mg/kg/day of liposomal amphotericin B) have been discussed for the treatment of select, invasive infections such as mucormycosis [95,96]. In such settings, the full target dose should be administered at the initiation of therapy (rather than titrated over several days). (See "Mucormycosis (zygomycosis)".)

For treatment of cryptococcal meningitis, preliminary data suggested that liposomal amphotericin B at doses of 10 mg/kg/day were well-tolerated and could allow for less frequent dosing or shorter courses of therapy [97]. A phase 3 randomized, controlled, noninferiority trial conducted in Africa reported that a single IV dose of liposomal amphotericin B,10mg/kg/day, combined with flucytosine and fluconazole for 14 days as initial induction therapy was as effective as standard therapy of amphotericin B deoxycholate plus flucytosine for seven days followed by fluconazole for seven days for the treatment of cryptococcal meningitis in patients with HIV (see "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention") [98]. Dosing for specific indications is discussed in specific UpToDate topics and in Lexicomp drug monographs.

Availability and cost — A 2016 investigation 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 [99]. In this report, the daily cost of amphotericin B deoxycholate amphotericin B ranged from <$1 to $171 (USD).

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 [100]. 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 [101,102]. Most recently, costs and resource use data were collected from 814 patients enrolled in the AMBITION-cm trial from hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe [102]. Mean total costs were USD $1369 (95% CI 1314 to 1424) and $1237 (1181 to 1293) per participant in the AmBisome and control groups, respectively. The incremental cost-effectiveness ratio was $128 (59 to 257) per life-year saved.

Amphotericin B plus fat emulsions — It has been suggested that mixing amphotericin B deoxycholate with fat emulsions may reduce renal dysfunction [60] and infusion-related reactions. However, incomplete and conflicting data exist regarding the safety, efficacy, and stability of these mixtures [103]. 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 [5].

SUMMARY

●Mechanism of action – 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 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.)

●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. 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.)

●Patient-population – 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.)

●Route of administration – 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.)

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

●Adverse effects – 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 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 'Use of lipid-based formulations'.)

●Dosing – The recommended dosing of the various formulations of amphotericin B for specific fungal diseases is discussed in detail in UpToDate topics and Lexi-Comp drug monographs. (See 'Introduction' above.)