Amphotericin B (Monograph)

Brand names: Abelcet, AmBisome
Drug class: Polyenes
- Antiprotozoal Agents
VA class: AM700
CAS number: 1397-89-3

Medically reviewed by Drugs.com on Sep 30, 2024. Written by ASHP.

Introduction

Antifungal; macrocyclic polyene.

Uses for Amphotericin B

Aspergillosis

Treatment of invasive aspergillosis caused by Aspergillus.

IDSA and others consider voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients, including HIV-infected patients. IV amphotericin B liposomal or isavuconazonium sulfate (prodrug of isavuconazole) are the preferred alternatives for primary treatment; IV amphotericin B lipid complex is another alternative.

For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends IV amphotericin B (a lipid formulation), an IV echinocandin (caspofungin, micafungin), oral or IV posaconazole, or itraconazole oral suspension.

IDSA states that IV amphotericin B (conventional or lipid formulations) is appropriate option for initial and salvage treatment of invasive aspergillosis when voriconazole cannot be used; however, reserve conventional IV amphotericin B for use in resource-limited settings when no other alternatives available.

For HIV-infected adults and adolescents with invasive aspergillosis, CDC, NIH, and IDSA recommend voriconazole as drug of choice; IV amphotericin B (conventional or lipid formulation), IV echinocandins (anidulafungin, caspofungin, micafungin), and oral posaconazole are alternatives.

Consult current IDSA clinical practice guidelines available at [Web] and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] for additional information on management of aspergillosis.

Blastomycosis

Treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis. A drug of choice.

IV amphotericin B is preferred for initial treatment of severe blastomycosis, especially infections involving the CNS, and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals. Oral itraconazole is the drug of choice for treatment of mild to moderate pulmonary blastomycosis or mild to moderate disseminated blastomycosis (without CNS involvement) and also recommended for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B.

Either conventional IV amphotericin B or a lipid formulation can be used for initial treatment of blastomycosis. However, IDSA and others state that a lipid formulation (e.g., amphotericin B liposomal) is preferred for treatment of CNS blastomycosis since higher CSF concentrations may be obtained.

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of blastomycosis.

Candida Infections

Treatment of disseminated or invasive infections caused by Candida, including candidemia, cardiovascular infections (endocarditis, pericarditis, myocarditis), or meningitis, and other serious Candida infections, including osteoarticular infections (osteomyelitis, septic arthritis), peritonitis, intra-abdominal abscesses, urinary tract infections (symptomatic cystitis, pyelonephritis, urinary fungus balls), and endophthalmitis. Also used for treatment of certain severe or refractory mucocutaneous Candida infections^{† [off-label]}.

Generally effective against infections caused by C. albicans, C. glabrata, C. krusei, C. parapsilosis, or C. tropicalis. A drug of choice for many infections caused by fluconazole-resistant Candida.

For treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis^{† [off-label]} in nonneutropenic patients in intensive care units (ICUs), IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) for initial therapy; IV or oral fluconazole is an acceptable alternative for initial treatment in selected patients, including those who are not critically ill and unlikely to have infections caused by fluconazole-resistant Candida. IV amphotericin B (a lipid formulation) recommended if echinocandin- and azole-resistant Candida suspected and is an alternative when echinocandins and fluconazole have been ineffective or cannot be used. Consider transition from echinocandin (or amphotericin B) to fluconazole (usually within 5–7 days) in clinically stable patients if strain susceptible to fluconazole (e.g., C. albicans) and initial treatment resulted in negative repeat blood cultures.

For treatment of candidemia in neutropenic patients, IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) or, alternatively, IV amphotericin B (a lipid formulation) for initial therapy. Fluconazole is an alternative in those who are not critically ill and have had no prior exposure to azole antifungals; also can be used for step-down therapy in clinically stable patients who have fluconazole-susceptible isolates and documented bloodstream clearance. Voriconazole can be used as an alternative for initial therapy when broader antifungal coverage is required and also can be used as step-down therapy during neutropenia in clinically stable patients who have voriconazole-susceptible isolates and documented bloodstream clearance. An echinocandin, amphotericin B (a lipid formulation), or voriconazole recommended for infections caused by C. krusei.

For treatment of chronic disseminated (hepatosplenic) candidiasis, IDSA recommends initial treatment with IV amphotericin B (a lipid formulation) or an IV echinocandin (anidulafungin, caspofungin, micafungin) followed by oral fluconazole therapy.

For treatment of CNS candidiasis, IDSA recommends initial treatment with IV amphotericin B liposomal (with or without oral flucytosine) and step-down treatment with fluconazole. Remove infected CNS devices (e.g., ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, biopolymer wafers that deliver chemotherapy) if possible. If a ventricular device cannot be removed, IDSA states conventional amphotericin B can administered through the device. Conventional amphotericin B has been given intrathecally^{† [off-label]} as an adjunct to systemic antifungal for treatment of Candida meningitis.

For treatment of neonatal candidiasis, including CNS infections, conventional IV amphotericin B usually is the drug of choice. Although not routinely recommended in neonates, concomitant use of flucytosine can be considered as salvage therapy if CNS infection does not respond to initial therapy with IV amphotericin B alone. IDSA and AAP state that fluconazole can be considered for step-down treatment after initial response obtained with IV amphotericin B. Fluconazole also a reasonable alternative for initial treatment of neonatal candidiasis without CNS involvement, provided patient had not been receiving fluconazole prophylaxis and causative agent is susceptible. Although lipid formulations of IV amphotericin B can be considered alternatives for treatment of neonatal candidiasis, use such formulations with caution, particularly if urinary tract involved.

For treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida, IDSA recommends initial treatment with a lipid formulation of IV amphotericin B (with or without oral flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin) and step-down treatment with fluconazole. If isolate is susceptible, long-term suppressive or maintenance therapy (secondary prophylaxis) with fluconazole recommended to prevent recurrence in those with native valve endocarditis who cannot undergo valve replacement and in those with prosthetic valve endocarditis.

Mucocutaneous or noninvasive Candida infections (e.g., oropharyngeal, esophageal, or vaginal candidiasis) usually can be adequately treated with an appropriate oral or topical antifungal. Severe mucocutaneous infections (e.g., oropharyngeal candidiasis^{† [off-label]}, esophageal candidiasis^{† [off-label]}) caused by azole-resistant Candida or infections that fail to respond to such therapy may require IV amphotericin B. Also has been recommended as an alternative for treatment of esophageal candidiasis^† in patients who cannot tolerate oral therapy.

IDSA states antifungal treatment not usually indicated for asymptomatic cystitis, unless there is high risk of disseminated candidiasis (e.g., neutropenic patients, low birthweight infants [<1.5 kg], patients undergoing urologic manipulations). If treatment is indicated, fluconazole usually drug of choice for symptomatic cystitis, pyelonephritis, or fungus balls likely to be caused by fluconazole-susceptible Candida. If symptomatic cystitis caused by fluconazole-resistant Candida, conventional IV amphotericin B or oral flucytosine recommended for C. glabrata and conventional IV amphotericin B recommended for C. krusei.

Conventional amphotericin B has been administered by bladder irrigation^† for treatment of candiduria (funguria), but such therapy is controversial. IDSA states that bladder irrigation^† with conventional amphotericin B is not generally recommended, but may be useful for patients with refractory symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata, C. krusei) or as an adjunct to systemic antifungal therapy for the treatment of urinary fungus balls,

Treatment of endophthalmitis^† caused by Candida. IDSA states that IV amphotericin B liposomal (with or without flucytosine) is the regimen of choice for endophthalmitis caused by fluconazole- and voriconazole-resistant Candida; fluconazole is an acceptable alternative for less severe endophthalmitis. In those with macular involvement, intravitreal^† administration of conventional amphotericin B also recommended to ensure prompt high levels of antifungal activity.

Treatment of infections caused by C. auris, an emerging pathogen associated with potentially fatal candidemia or other invasive infections. If C. auris infection suspected, immediately contact state or local public health authorities and the CDC (candidaauris@cdc.gov) for guidance. Consult interim recommendations and most recent information from CDC available at [Web] for additional information on diagnosis and management of C. auris infections.

Coccidioidomycosis

Treatment of coccidioidomycosis caused by Coccidioides immitis or C. posadasii.

IDSA states antifungal treatment not considered necessary in patients with newly diagnosed, uncomplicated coccidioidal pneumonia who have mild or nondebilitating symptoms, including those with an asymptomatic pulmonary nodule or cavity due to coccidioidomycosis and no overt immunocompromising conditions. Antifungal treatment recommended for patients with symptomatic chronic cavitary coccidioidal pneumonia, ruptured coccidioidal cavities, extrapulmonary soft tissue coccidioidomycosis, bone and joint coccidioidomycosis, or coccidioidal meningitis. Antifungal treatment also usually recommended for immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).

For initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis, an oral azole (fluconazole or itraconazole) usually recommended. IV amphotericin B recommended as an alternative and is preferred for initial treatment of severely ill patients who have rapidly progressing disease or extrathoracic disseminated disease, for immunocompromised individuals, or when azole antifungals cannot be used (e.g., pregnant women).

For HIV-infected adults, adolescents, or children with clinically mild coccidioidomycosis (e.g., focal pneumonia), CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole for initial treatment. For treatment of severe (nonmeningeal) coccidioidomycosis (e.g., diffuse pulmonary infections or extrathoracic disseminated infections) in HIV-infected adults, adolescents, or children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B (conventional or lipid formulation) followed by an oral azole. Alternatively, some experts recommend initial treatment with IV amphotericin B in conjunction with an oral azole (fluconazole or itraconazole) followed by the oral azole alone.

For treatment of coccidioidal meningitis in HIV-infected adults, adolescents, or children or other individuals, fluconazole (with or without intrathecal^† conventional amphotericin B) is the regimen of choice; other oral azoles (itraconazole, posaconazole, voriconazole) considered alternatives in adults and adolescents. If patient does not respond to azole therapy alone, consider intrathecal^† conventional amphotericin B (with or without continued azole therapy) or IV amphotericin B used in conjunction with intrathecal^† conventional amphotericin B. Consultation with an expert recommended.

Long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole recommended to prevent relapse or recurrence of coccidioidomycosis in HIV-infected individuals who have been adequately treated for the disease. Secondary prophylaxis with oral fluconazole or oral itraconazole also necessary in any other individual treated for coccidioidal meningitis.

Cryptococcosis

Treatment of infections caused by Cryptococcus neoformans. A drug of choice, especially for initial treatment of meningitis. Because of reported in vitro and in vivo synergism, usually used in conjunction with flucytosine for initial treatment, including in HIV-infected patients.

Although conventional IV amphotericin has been the preferred amphotericin B formulation for treatment of cryptococcosis, IV amphotericin B liposomal may now be preferred, especially in patients with or predisposed to renal dysfunction. Can use conventional IV amphotericin B if cost is an issue and risk of renal dysfunction is low. Although data limited, IV amphotericin B lipid complex considered an alternative to IV amphotericin B liposomal or conventional IV amphotericin B for treatment of cryptococcosis.

For HIV-infected adults, adolescents, and children with cryptococcal meningitis, CDC, NIH, and IDSA and others state that the preferred regimen is initial (induction) therapy with IV amphotericin B (liposomal or conventional formulation) given in conjunction with flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral fluconazole given for at least 8 weeks, followed by long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to complete at least 1 year of azole therapy.

Alternative regimens for initial (induction) therapy for treatment of cryptococcal meningitis in HIV-infected adults and adolescents who cannot receive the preferred regimen are IV amphotericin B lipid complex in conjunction with oral flucytosine; IV amphotericin B (liposomal or conventional formulation) in conjunction with oral or IV fluconazole; IV amphotericin B (liposomal or conventional formulation) alone; oral or IV fluconazole in conjunction with oral flucytosine; or oral or IV fluconazole alone.

Alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen. IDSA states that use of intrathecal^† or intraventricular^† conventional amphotericin B in the treatment of cryptococcal meningitis generally is discouraged and rarely necessary.

For treatment of cryptococcal CNS infections in organ transplant recipients, IDSA recommends induction therapy with IV amphotericin B liposomal or amphotericin B lipid complex given in conjunction with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole given for 8 weeks. Induction regimen should be continued for at least 4–6 weeks if flucytosine isn't included. Conventional amphotericin B not usually recommended for first-line treatment of cryptococcosis in transplant recipients because of the risk of nephrotoxicity.

In adults and children who do not have HIV infection and are not transplant recipients, IDSA states that the preferred regimen for treatment of cryptococcal meningitis is induction therapy with conventional IV amphotericin B given in conjunction with oral flucytosine for at least 4 weeks (consider a 2-week induction period in those who are immunocompetent, are without uncontrolled underlying disease, and are at low risk for therapeutic failure), then consolidation therapy with oral fluconazole administered for an additional 8 weeks or longer.

For treatment of mild to moderate pulmonary cryptococcosis (nonmeningeal) in immunocompetent or immunosuppressed adults or children, IDSA states that the regimen of choice is oral fluconazole given for 6–12 months. However, severe pulmonary cryptococcosis, cryptococcemia, and disseminated cryptococcal infections in immunocompetent or immunosuppressed adults, adolescents, or children should be treated using regimens recommended for cryptococcal meningitis.

Long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole recommended to prevent relapse or recurrence of cryptococcosis in HIV-infected adults, adolescents, or children who have been adequately treated for the disease. Oral itraconazole is an alternative in those who cannot tolerate fluconazole, but may be less effective than fluconazole in preventing relapse of cryptococcosis. Conventional IV amphotericin B has been used for secondary prophylaxis (e.g., in individuals who cannot receive azole antifungals), but is less effective and associated with IV catheter-related infections.

Although data are limited, IDSA states that recommendations for treatment of CNS or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.

Exserohilum Infections

Treatment of infections known or suspected to be caused by Exserohilum rostratum^†.

Exserohilum, a common mold found in soil and on plants (especially grasses), is rarely involved in human infections. E. rostratum has caused cutaneous and subcutaneous infections or keratitis, typically from skin or eye trauma; also has rarely caused more invasive or life-threatening infections (e.g., sinuses, heart, lungs, bones), usually in immunocompromised individuals. Exserohilum infections cannot be transmitted person-to-person.

Although data limited and clinical relevance of in vitro testing remains uncertain, Exserohilum is inhibited in vitro by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B; echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity and fluconazole has poor in vitro activity against the fungus.

E. rostratum was a predominant pathogen in the 2012–2013 US outbreak of fungal meningitis and other fungal infections in patients who received contaminated preservative-free methylprednisolone acetate injections prepared by a compounding pharmacy (New England Compounding Center [NECC]).

As of October 30, 2015, total of 753 cases of fungal infections (including 64 deaths) reported in 20 states and linked to specific lots of contaminated methylprednisolone acetate injections. Majority of initial cases involved fungal meningitis (some with stroke); subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess). More than 6 months after the outbreak, CDC continued to receive reports of patients presenting with localized spinal and paraspinal infections (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, arachnoiditis, or other complications at or near the injection site). Some localized infections occurred in patients with or without a diagnosis of fungal meningitis.

Consultation with an infectious disease expert recommended to assist with diagnosis, management, and follow-up, which may be complex and prolonged. Clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636.

Because of evidence of latent disease, CDC cautions clinicians to remain vigilant for possibility of infections in patients who received injections of NECC products and to consider such infections in the differential diagnosis when evaluating symptomatic patients who received such products. CDC recommends routine laboratory and microbiologic tests, including bacterial and fungal cultures, as necessary; consider MRI evaluation if clinically warranted.

For treatment of CNS infections (including meningitis, stroke, and arachnoiditis) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) in adults who received contaminated corticosteroid injections, CDC recommends voriconazole. Strongly consider use of IV amphotericin B liposomal in addition to voriconazole in patients who present with severe disease and in those who do not improve or experience clinical deterioration or manifest new sites of disease activity while receiving voriconazole monotherapy. IV amphotericin B liposomal also recommended as an alternative in patients unable to tolerate voriconazole.

For treatment of osteoarticular infections (discitis, vertebral osteomyelitis, and epidural abscess or osteoarticular infections not involving the spine) in adults who received intra-articular injections of contaminated corticosteroid products, CDC recommends voriconazole. Consider use of a lipid formulation of IV amphotericin B in addition to IV voriconazole in patients with severe osteoarticular infection and/or clinical instability. A lipid formulation of IV amphotericin B, posaconazole, or itraconazole recommended as alternatives in patients who cannot tolerate voriconazole; expert consultation advised when making decisions regarding alternative regimens.

Adequate duration of antifungal treatment for infections associated with contaminated corticosteroid injections not known, but prolonged therapy (at least 3–6 months) required. (See Exserohilum Infections under Dosage and Administration.) Close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.

Consult CDC website at [Web] for most recent information regarding diagnosis and treatment of these infections.

Fusarium Infections

Treatment of serious fungal infections caused by Fusarium. A drug of choice.

Select most appropriate antifungal based on in vitro susceptibility testing. Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides; either voriconazole or amphotericin B recommended for other Fusarium infections. Consider concomitant use of amphotericin B and voriconazole in patients with severe infections or immunosuppression.

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum.

IV amphotericin B and oral itraconazole are the drugs of choice for treatment of histoplasmosis, including in HIV-infected individuals. IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients (e.g., those with HIV infection). Oral itraconazole generally used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in severe infections after a response has been obtained with amphotericin B.

For HIV-infected adults and adolescents with moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis, CDC, NIH, and IDSA recommend initial (induction) treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole. Alternatively, if necessary because of cost or tolerability, IV amphotericin B lipid complex can be used.

For treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole; conventional IV amphotericin B can be used as an alternative to the lipid formulation for initial treatment in these children. Although oral itraconazole may be used alone for treatment of mild to moderate disseminated histoplasmosis in children, including HIV-infected infants and children, it is not recommended for more severe infections.

For treatment of meningitis caused by H. capsulatum in HIV-infected adults, adolescents, or children and in other individuals, CDC, NIH, and IDSA recommend initial (induction) treatment with IV amphotericin B liposomal and follow-up treatment with oral itraconazole. Amphotericin B liposomal generally preferred for treatment of CNS histoplasmosis because higher CSF concentrations may be obtained than with some other amphotericin B formulations.

Long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole recommended to prevent relapse or recurrence of histoplasmosis in HIV-infected adults, adolescents, and children and other immunosuppressed individuals who have been adequately treated for histoplasmosis.

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis^† (South American blastomycosis) caused by Paracoccidioides brasiliensis.

IV amphotericin B is drug of choice for initial treatment of severe paracoccidioidomycosis. Oral itraconazole is drug of choice for treatment of less severe or localized paracoccidioidomycosis and for follow-up therapy in more severe infections after initial treatment with IV amphotericin B.

Penicilliosis

Treatment of penicilliosis^† caused by Penicillium marneffei.

For treatment of severe or disseminated P. marneffei infections, an initial regimen of IV amphotericin B followed by oral itraconazole recommended. Oral itraconazole can be used alone for treatment of mild infections.

For HIV-infected adults and adolescents with severe acute penicilliosis^†, CDC, NIH, and IDSA recommend treatment with IV amphotericin B liposomal initially followed by oral itraconazole. Voriconazole is an alternative, and may be used in those who do not respond to amphotericin B followed by itraconazole.

Long-term suppressive or maintenance therapy (secondary prophylaxis) with itraconazole recommended to prevent relapse of penicilliosis in HIV-infected adults and adolescents who were treated for penicilliosis.

Consult current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] for additional information on management of penicilliosis.

Sporotrichosis

Treatment of disseminated, pulmonary, osteoarticular, and meningeal sporotrichosis caused by Sporothrix schenckii.

IV amphotericin B is the drug of choice for initial treatment of severe, life-threatening sporotrichosis and sporotrichosis that is disseminated or has CNS involvement. Oral itraconazole is considered the drug of choice for treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up treatment of severe infections after a response has been obtained with IV amphotericin B.

IDSA and others state that a lipid formulation of amphotericin B is preferred for treatment of sporotrichosis since the lipid formulations generally are associated with fewer adverse effects.

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of sporotrichosis.

Zygomycosis

Treatment of zygomycosis, including mucormycosis, caused by susceptible species of Lichtheimia (formerly Absidia), Mucor, or Rhizopus and treatment of infections caused by susceptible species of Conidiobolus or Basidiobolus.

Drug of choice for zygomycosis. However, severe cases of GI basidiobolomycosis caused by Basidiobolus ranarum may not respond to amphotericin B. GI basidiobolomycosis has been successfully treated with oral itraconazole after partial surgical resection of the GI tract.

Empiric Therapy in Febrile Neutropenic Patients

Empiric therapy of presumed fungal infections in febrile, neutropenic patients^† who have not responded to empiric treatment with broad-spectrum antibacterial agents.

Conventional IV amphotericin B historically has been the drug of choice for empiric antifungal treatment in patients who remain febrile and neutropenic despite 4–7 days of empiric treatment with an appropriate broad-spectrum antibacterial agent; lipid formulations of amphotericin B or other antifungals (e.g., caspofungin, voriconazole) also have been used.

Consult published protocols on treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of initial empiric regimen, when to change initial regimen, possible subsequent regimens, and duration of therapy in these patients. Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also advised.

Prevention of Fungal Infections in Transplant Recipients, Cancer Patients, or Other Patients at High Risk

Prevention of fungal infections^† (e.g., aspergillosis, candidiasis) in neutropenic cancer patients^† or patients undergoing BMT^† or solid organ transplantation^†.

For postoperative antifungal prophylaxis in recipients of solid organ transplants^† at high risk for invasive candidiasis (i.e., liver, pancreas, or small bowel transplant recipients), IDSA recommends fluconazole or IV amphotericin B liposomal. Risk of invasive candidiasis after other solid organ transplants (e.g., kidney, heart) appears to be too low to warrant routine antifungal prophylaxis.

Conventional amphotericin B, amphotericin B lipid complex, and amphotericin B liposomal have been administered by nasal instillation^† or nebulization^† in an attempt to prevent aspergillosis in immunocompromised patients, including solid organ transplant recipients^† (e.g., lung transplant recipients) and neutropenic chemotherapy patients^†.

Leishmaniasis

Treatment of American cutaneous leishmaniasis, including infections caused by Leishmania braziliensis or L. mexicana, and treatment of mucocutaneous leishmaniasis, including infections caused by L. braziliensis. Drugs of choice for cutaneous or mucocutaneous leishmaniasis are sodium stibogluconate (not commercially available in the US, but may be available from CDC), meglumine antimonate (not commercially available in the US), and miltefosine; amphotericin B is an additional drug of choice for mucosal infections.

Treatment of visceral leishmaniasis (also known as kala-azar). Drugs of choice for initial treatment of visceral leishmaniasis caused by L. donovani (usually endemic in Asia and Africa), L. infantum (usually endemic in the Mediterranean basin), or L. chagasi (usually endemic in Latin America) are amphotericin B (a lipid formulation), sodium stibogluconate (not commercially available in the US, but may be available from CDC), meglumine antimonate (not commercially available in the US), and miltefosine; amphotericin B (conventional formulation) is considered an alternative.

Leishmaniasis is caused by >15–20 different Leishmania species that are transmitted to humans by bite of infected sand flies; also can be transmitted via blood (e.g., blood transfusions, needles shared by IV drug abusers) and perinatally from mother to infant. In Eastern Hemisphere (Old World), leishmaniasis found most frequently in parts of Asia, the Middle East, Africa, and southern Europe; in Western Hemisphere (New World), found most frequently in Mexico and Central and South America and reported occasionally in Texas and Oklahoma. Leishmaniasis reported in short-term travelers to endemic areas and in immigrants and expatriates from such areas; also reported in US military personnel and contract workers serving or working in endemic areas (e.g., Iraq, Afghanistan).

Specific form of leishmaniasis and disease severity depend on Leishmania species involved, geographic area of origin, location of sand fly bite, and patient factors (e.g., nutritional and immune status). Treatment (e.g., drug, dosage, duration of treatment) must be individualized based on region where disease was acquired, likely infecting species, drug susceptibilities reported in area of origin, form of disease, and patient factors (e.g., age, pregnancy, immune status). No single treatment approach is appropriate for all possible clinical presentations. Consultation with clinicians experienced in management of leishmaniasis recommended.

For HIV-infected adults and adolescents with cutaneous leishmaniasis, CDC, NIH, and IDSA recommend amphotericin B liposomal^† or sodium stibogluconate (not commercially available in the US, but may be available from CDC) as the drugs of choice for treatment. Possible alternatives include miltefosine, topical paromomycin (not available in the US), intralesional pentavalent antimony (not available in the US), or local heat therapy.

For HIV-infected adults and adolescents with visceral leishmaniasis, CDC, NIH, and IDSA recommend amphotericin B liposomal as the drug of choice for treatment; treatment alternatives include amphotericin B lipid complex^†, conventional amphotericin B^†, sodium stibogluconate (not commercially available in the US, but may be available from CDC), or miltefosine.

Long-term suppressive or maintenance therapy (secondary prophylaxis)^† to decrease the risk of relapse in HIV-infected individuals who have been treated for visceral leishmaniasis and have CD4⁺ T-cell count <200/mm³. Although data limited, secondary prophylaxis also may be indicated in HIV-infected individuals who have been adequately treated for cutaneous leishmaniasis but are immunocompromised and have had multiple relapses. If secondary prophylaxis against leishmaniasis is indicated, CDC, NIH, and IDSA recommend amphotericin B liposomal^† or amphotericin B lipid complex^†; the alternative is sodium stibogluconate (not commercially available in the US, but may be available from CDC). Manufacturer of amphotericin B liposomal states that efficacy and safety of repeated courses or maintenance therapy with the drug in immunocompromised individuals not evaluated to date.

For assistance with diagnosis or treatment of leishmaniasis in the US, contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays. Contact CDC Drug Service at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in US.

Primary Amebic Meningoencephalitis

Treatment of primary amebic meningoencephalitis caused by Naegleria fowleri^†, a free-living ameba.

CNS infections caused by free-living ameba associated with high mortality rate; early diagnosis and aggressive treatment may increase chance of survival. Although data limited, most reported cases of N. fowleri have been treated empirically with multiple-drug regimens. Regimens used or recommended include several anti-infectives (e.g., amphotericin B, azole antifungals [fluconazole], flucytosine, macrolides [azithromycin, clarithromycin], miltefosine, rifampin) and other therapies (e.g., dexamethasone, phenytoin, therapeutic hypothermia).

Based on multiple-drug regimens used to date in documented survivors, CDC recommends anti-infective regimen that includes conventional amphotericin B (administered IV and intrathecally^†), azithromycin, fluconazole, miltefosine, and rifampin for treatment of primary amebic meningoencephalitis caused by N. fowleri. Because of evidence that amphotericin B liposomal may be less effective than conventional amphotericin B for treatment of amebic meningoencephalitis in mice, conventional formulation preferred if amphotericin B used for treatment of primary amebic meningoencephalitis caused by N. fowleri.

For assistance with diagnosis or treatment of suspected free-living ameba infections, contact CDC Emergency Operations Center at 770-488-7100.

Amphotericin B Dosage and Administration

Administration

Administer conventional amphotericin B, amphotericin B lipid complex, and amphotericin B liposomal by IV infusion. (See Acute Infusion Reactions under Cautions.)

Conventional amphotericin B also has been given intra-articularly^†, intrapleurally^†, intrathecally^†, by nasal instillation^† or nebulization^†, and by bladder irrigation^†. Amphotericin B lipid complex and amphotericin B liposomal also have been administered by nasal inhalation^† or nebulization^†.

IV Administration of Conventional Amphotericin B

Reconstitution and Dilution

Conventional amphotericin B must be reconstituted and diluted prior to administration.

Reconstitute 50-mg vial by adding 10 mL of sterile water for injection (without bacteriostatic agent) to provide a solution containing 5 mg/mL. Add sterile water diluent rapidly to the vial using a sterile syringe and 20-gauge needle; immediately shake vial until colloidal dispersion is clear.

For IV infusion, the colloidal dispersion is further diluted (usually to a concentration of 0.1 mg/mL) with 500 mL of 5% dextrose injection (the dextrose injection must have a pH exceeding 4.2). Although pH of commercially available 5% dextrose injection usually is >4.2, pH of each container of 5% dextrose injection should be determined and, if pH is low, it may be adjusted with a sterile buffer solution in accordance with instructions provided by the manufacturers.

Rate of Administration

Administer conventional amphotericin B by IV infusion slowly over a period of approximately 2–6 hours, depending on dose.

IV infusions given over 1–2 hours may be tolerated in some patients, but manufacturers and many clinicians state that rapid IV infusion should be avoided since potentially serious adverse effects (e.g., hypotension, hypokalemia, arrhythmias, shock) may occur.

An inline membrane filter may be used; to ensure passage of amphotericin B colloidal dispersion, the mean pore diameter of the filter should not be <1 µm.

IV Administration of Amphotericin B Lipid Complex (Abelcet)

Dilution

Amphotericin B lipid complex suspension concentrate must be diluted prior to administration.

Dilute in 5% dextrose injection to a concentration of 1 mg/mL according to the manufacturer's directions; a concentration of 2 mg/mL may be appropriate for pediatric patients and patients with cardiovascular disease.

Do not use solutions containing sodium chloride or bacteriostatic agents; do not mix with other drugs or with electrolytes.

Prior to administration, shake IV container of diluted drug until contents are thoroughly mixed; shake infusion container every 2 hours if infusion time is >2 hours.

Administer using a separate infusion line; if an existing IV line is used, flush with 5% dextrose injection before amphotericin B lipid complex is infused.

Do not use an inline membrane filter during administration of amphotericin B lipid complex.

Rate of Administration

Administer amphotericin B lipid complex by IV infusion at a rate of 2.5 mg/kg per hour.

IV Administration of Amphotericin B Liposomal (AmBisome)

Reconstitution and Dilution

Amphotericin B liposomal must be reconstituted prior to administration.

Reconstitute 50-mg vial by adding 12 mL of sterile water for injection to provide a solution containing 4 mg/mL. Do not use other diluents (e.g., diluents containing sodium chloride or a bacteriostatic agent) to reconstitute amphotericin B liposomal; do not admix reconstituted solution with other drugs.

For IV infusion, reconstituted solution should be further diluted. Withdraw the appropriate amount of reconstituted solution into a sterile syringe and attach the 5-µm sterile, disposable filter provided by the manufacturer. Inject the syringe contents through the filter into the appropriate volume of 5% dextrose injection to provide a final concentration of 1–2 mg/mL. Lower concentrations (0.2–0.5 mg/mL) may be appropriate for infants and small children.

May be infused through an in-line membrane filter, provided the mean pore diameter of the filter is ≥1 µm.

May be administered through an existing IV line; the line must be flushed with 5% dextrose injection prior to infusion of the antifungal. If this is not feasible, amphotericin B liposomal must be administered through a separate line.

Rate of Administration

Administer amphotericin B liposomal by IV infusion over a period of approximately 2 hours using a controlled infusion device. If the infusion is well tolerated, infusion time may be reduced to approximately 1 hour; duration of infusion should be increased in patients who experience discomfort during infusion.

Dosage

Available as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B lipid complex (Abelcet), or amphotericin B liposomal (AmBisome); dosage is expressed as amphotericin B.

Dosage varies depending on whether the drug is administered as conventional amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal. Follow dosage recommendations for the specific formulation being administered.

Prior to initiation of conventional IV amphotericin B therapy, a single test dose of the drug (1 mg in 20 mL of 5% dextrose injection) can be administered IV over 20–30 minutes and the patient carefully monitored (i.e., pulse and respiration rate, temperature, blood pressure) every 30 minutes for 2–4 hours. In patients with good cardiorenal function who tolerate the test dose, therapy usually initiated with a daily dosage of 0.25 mg/kg (0.3 mg/kg in those with severe or rapidly progressing fungal infections) given as a single daily dose. In patients with impaired cardiorenal function and in patients who have severe reactions to the test dose, therapy should be initiated with a smaller daily dosage (i.e., 5–10 mg). Depending on patient’s cardiorenal status, dosage may gradually be increased by 5–10 mg daily to a final daily dosage of 0.5–0.7 mg/kg.

Pediatric Patients

General Pediatric Dosage

Treatment of Invasive Fungal Infections

Conventional amphotericin B: AAP recommends 1–1.5 mg/kg once daily. Use lowest effective dosage.

Amphotericin B lipid complex: 5 mg/kg once daily.

Amphotericin B liposomal: 3–5 mg/kg daily.

Aspergillosis

Treatment of Aspergillosis

Conventional amphotericin B in HIV-infected adolescents: 1 mg/kg once daily continued at least until CD4⁺ T-cell count >200/mm³ and there is evidence of resolution of aspergillosis.

Amphotericin B (a lipid formulation) in HIV-infected adolescents: 5 mg/kg once daily continued at least until CD4⁺ T-cell count >200/mm³ and there is evidence of resolution of aspergillosis.

Amphotericin B lipid complex: 5 mg/kg once daily.

Amphotericin B liposomal in children ≥1 month of age: 3–5 mg/kg once daily.

Optimal duration of therapy uncertain. IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks.

Blastomycosis

Treatment of Severe Blastomycosis

Conventional amphotericin B: IDSA recommends 0.7–1 mg/kg once daily, followed by oral itraconazole for total treatment duration of 12 months.

Amphotericin B (a lipid formulation): IDSA recommends 3–5 mg/kg once daily, followed by oral itraconazole for total treatment duration of 12 months.

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Conventional amphotericin B: 0.5–1 mg/kg daily. Usual duration of treatment for candidemia is 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.

Amphotericin B lipid complex: 5 mg/kg once daily.

Amphotericin B liposomal in children ≥1 month of age: 3–5 mg/kg once daily. Median duration in clinical studies has been 15–29 days; some Candida infections have been effectively treated with a median duration of 5–7 days.

Treatment of Neonatal Candidiasis

Conventional amphotericin B: 1 mg/kg daily for 2 weeks after documented clearance of Candida from the bloodstream and resolution of candidemia symptoms. If CNS involved, continue antifungal until resolution of all signs, symptoms, and CSF and radiologic abnormalities (if present).

Treatment of Severe or Refractory Oropharyngeal Candidiasis†

Conventional amphotericin B in HIV-infected adolescents: 0.3 mg/kg daily.

Treatment of Esophageal Candidiasis†

Conventional amphotericin B in HIV-infected infants and children: 0.3–0.7 mg/kg once daily for at least 3 weeks and for at least 2 weeks after resolution of symptoms.

Conventional amphotericin B in HIV-infected adolescents: 0.6 mg/kg daily for 14–21 days.

Amphotericin B (a lipid formulation) in HIV-infected adolescents: 3–4 mg/kg daily for 14–21 days.

Coccidioidomycosis

Treatment of Coccidioidomycosis (Nonmeningeal)

Conventional amphotericin B in HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis: 0.5–1 mg/kg once daily.

Conventional amphotericin B in HIV-infected adolescents with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 0.7–1 mg/kg daily.

Amphotericin B (a lipid formulation) in HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis: 5 mg/kg once daily.

Amphotericin B (a lipid formulation) in HIV-infected adolescents with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 4–6 mg/kg daily.

Continue treatment with amphotericin B (conventional or lipid formulation) until improvement occurs, then switch to follow-up treatment with oral fluconazole or oral itraconazole. Recommended total treatment duration is1 year.

HIV-infected children and adolescents who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole to prevent relapse or recurrence.

Cryptococcosis

Treatment of Cryptococcosis (Nonmeningeal)

Conventional amphotericin B in children with disseminated cryptococcosis: Induction therapy with 1 mg/kg daily given with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.

Conventional amphotericin B in HIV-infected infants and children with severe pulmonary or disseminated cryptococcosis: 0.7–1 mg/kg daily (with or without oral flucytosine).

Conventional amphotericin B in HIV-infected infants and children with localized disease (e.g., isolated pulmonary disease): 0.7–1 mg/kg daily (without oral flucytosine). Treatment duration depends on response and site and severity of infection.

Amphotericin B lipid complex in HIV-infected infants and children with severe pulmonary or disseminated cryptococcosis: 5 mg/kg daily (with or without oral flucytosine). Same dosage can be used without flucytosine for localized disease (e.g., isolated pulmonary disease). Treatment duration depends on response and site and severity of infection.

Amphotericin B liposomal in children ≥1 month of age: Manufacturer recommends 3–5 mg/kg once daily.

Amphotericin B liposomal in HIV-infected infants and children with severe pulmonary or disseminated cryptococcosis: 3–5 mg/kg daily (with or without oral flucytosine). Treatment duration depends on response and site and severity of infection.

Amphotericin B liposomal in HIV-infected infants and children with localized disease (e.g., isolated pulmonary disease): 3–5 mg/kg daily (without oral flucytosine). Treatment duration depends on response and site and severity of infection.

HIV-infected children and adolescents who have been adequately treated for cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to prevent relapse or recurrence.

Treatment of Cryptococcal Meningitis

Conventional amphotericin B in HIV-infected infants and children and other children: Induction therapy with 1 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Conventional amphotericin B in HIV-infected infants and children who cannot receive flucytosine: Induction therapy with 1–1.5 mg/kg daily given alone or with fluconazole for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Conventional amphotericin B in HIV-infected adolescents: Induction therapy with 0.7–1 mg/kg daily given with oral flucytosine for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Conventional amphotericin B in HIV-infected adolescents who cannot receive flucytosine: Induction therapy with 0.7–1 mg/kg daily given with oral or IV fluconazole or alone for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B lipid complex in HIV-infected infants, children, and adolescents: Induction therapy with 5 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B lipid complex in HIV-infected infants or children who cannot receive flucytosine: Induction therapy with 5 mg/kg daily given with oral fluconazole or alone for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B liposomal in HIV-infected children ≥1 month of age: Manufacturer recommends 6 mg/kg daily.

Amphotericin B liposomal in HIV-infected infants and children: Induction therapy with 6 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks. Same dosage can be used in children who cannot receive flucytosine.

Amphotericin B liposomal in HIV-infected infants or children who cannot receive flucytosine: Induction therapy with 6 mg/kg daily given with oral fluconazole or alone for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B liposomal in children with CNS and disseminated cryptococcal infections: Induction therapy with 5 mg/kg daily given with oral flucytosine for 2 weeks, then consolidation therapy with oral fluconazole given for at least 8 weeks. In children without HIV infection who are not transplant recipients, continue induction phase for at least 4 weeks (6 weeks in those with neurologic complications) before initiating consolidation regimen.

Amphotericin B liposomal in HIV-infected adolescents: Induction therapy with 3–4 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B liposomal in HIV-infected adolescents who cannot receive flucytosine: Induction therapy with 3–4 mg/kg daily given with oral or IV fluconazole or alone for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Conventional amphotericin B in HIV-infected adolescents who cannot receive fluconazole: 1 mg/kg once weekly. Initiate secondary prophylaxis after the primary infection has been adequately treated.

Histoplasmosis

Treatment of Histoplasmosis

Conventional amphotericin B for treatment of progressive disseminated histoplasmosis in children: IDSA recommends 1 mg/kg daily for 4–6 weeks or, alternatively, an initial regimen of 1 mg/kg daily given for 2–4 weeks then follow-up treatment with oral itraconazole for total treatment duration of 3 months.

Conventional amphotericin B for treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants or children: CDC, NIH, and IDSA recommend initial regimen of 0.7–1 mg/kg once daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for 12 months.

Amphotericin B lipid complex for treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adolescents: CDC, NIH, and IDSA recommend initial regimen of 5 mg/kg daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.

Amphotericin B liposomal for treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants, children, and adolescents: CDC, NIH, and IDSA recommend initial regimen of 3–5 mg/kg once daily given for at least 1–2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.

Amphotericin B liposomal for treatment of CNS histoplasmosis in HIV-infected infants, children, and adolescents: CDC, NIH, and IDSA recommend initial regimen of 5 mg/kg once daily for 4–6 weeks and follow-up treatment with oral itraconazole for at least 12 months and until abnormal CSF findings resolve and histoplasmal antigen is undetectable.

HIV-infected children and adolescents and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent relapse or recurrence.

Sporotrichosis

Treatment of Sporotrichosis

Conventional amphotericin B in children with disseminated sporotrichosis: Initial treatment with 0.7 mg/kg daily until a response is obtained, followed by oral itraconazole for total treatment duration of at least 12 months.

Leishmaniasis

Treatment of Cutaneous and Mucocutaneous Leishmaniasis

Conventional amphotericin B for cutaneous or mucosal leishmaniasis: 0.25–0.5 mg/kg daily initially; gradually increase dosage until 0.5–1 mg/kg daily is reached, at which time the drug usually is given on alternate days.

Conventional amphotericin B for mucosal disease: Some clinicians recommend 0.5–1 mg/kg daily or every other day for 4–8 weeks.

Duration of therapy depends on severity of disease and response to the drug, but generally is 3–12 weeks. Total treatment dose generally ranges from 1–3 g;

Treatment of Visceral Leishmaniasis (Kala-Azar)

Conventional amphotericin B^†: 0.5–1 mg/kg administered on alternate days for 14–20 doses has been used. Some clinicians recommend 1 mg/kg daily for 15–20 days or 1 mg/kg every second day for up to 8 weeks for total treatment dose of 15–20 mg/kg.

Amphotericin B liposomal in immunocompetent children ≥1 month of age: Manufacturer recommends 3 mg/kg once daily on days 1–5, then 3 mg/kg once daily on days 14 and 21; a second course of the drug may be useful if the infection is not completely cleared with a single course.

Amphotericin B liposomal in immunocompromised children ≥1 month of age: Manufacturer recommends 4 mg/kg once daily on days 1–5, then 4 mg/kg daily on days 10, 17, 24, 31, and 38; if the parasitic infection is not completely cleared after the first course or if relapses occur, consult an expert regarding further treatment.

Various other dosage regimens of amphotericin B liposomal have been used, including 10 mg/kg daily given on 2 consecutive days.

Treatment of Cutaneous Leishmaniasis in HIV-infected Adolescents

Amphotericin B liposomal^†: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg. Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.

Treatment of Visceral Leishmaniasis (Kala-Azar) in HIV-infected Adolescents

Conventional amphotericin B^†: 0.5–1 mg/kg daily for total treatment dose of 1.5–2 g.

Amphotericin B lipid complex^†: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg. Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.

Amphotericin B liposomal: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg. Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.

Prevention of Recurrence (Secondary Prophylaxis) of Visceral Leishmaniasis (Kala-Azar) in HIV-infected Adolescents†

Amphotericin B lipid complex: 3 mg/kg once every 21 days.

Amphotericin B liposomal: 4 mg/kg once every 2–4 weeks.

Initiate secondary prophylaxis after infection has been adequately treated.

Consideration can be given to discontinuing secondary prophylaxis if CD4⁺ T-cell count has remained >200–350/mm³ for ≥3–6 months. Some clinicians suggest secondary prophylaxis against leishmaniasis be continued indefinitely in HIV-infected individuals.

Adults

Aspergillosis

Treatment of Aspergillosis

Conventional amphotericin B: 0.5–1.5 mg/kg daily.

Conventional amphotericin B in HIV-infected adults: 1 mg/kg once daily continued at least until CD4⁺ T-cell count >200/mm³ and there is evidence of resolution of aspergillosis.

Amphotericin B (a lipid formulation) in HIV-infected adults: 5 mg/kg once daily continued at least until CD4⁺ T-cell count >200/mm³ and there is evidence of clinical response.

Amphotericin B lipid complex: 5 mg/kg once daily.

Amphotericin B liposomal: 3–5 mg/kg once daily. Higher dosage does not result in improved efficacy and is associated with an increased incidence of adverse effects (e.g., nephrotoxicity).

IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks.

Blastomycosis

Treatment of Moderate to Severe Pulmonary Blastomycosis

Conventional amphotericin B: 0.7–1 mg/kg daily for 1–2 weeks or until improvement occurs, followed by oral itraconazole for total treatment duration of 6–12 months.

Amphotericin B (a lipid formulation): 3–5 mg/kg daily for 1–2 weeks or until improvement occurs, followed by oral itraconazole therapy for total treatment duration of 6–12 months.

Treatment of Disseminated Extrapulmonary Blastomycosis (Without CNS Involvement)

Conventional amphotericin B: 0.7–1 mg/kg daily for 1–2 weeks or until improvement occurs, followed by oral itraconazole for total treatment duration of at least 12 months.

Amphotericin B (a lipid formulation): 3–5 mg/kg daily for 1–2 weeks or until improvement occurs, followed by oral itraconazole for total treatment duration of at least 12 months.

Treatment of CNS Blastomycosis

Amphotericin B (a lipid formulation): 5 mg/kg once daily for 4–6 weeks, followed by an oral azole (fluconazole, itraconazole, voriconazole) given for at least 12 months and until resolution of CSF abnormalities.

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Conventional amphotericin B: 0.5–1 mg/kg daily.

Amphotericin B (a lipid formulation) in nonneutropenic or neutropenic adults: IDSA recommends 3–5 mg/kg daily. Consider transitioning to fluconazole (usually within 5–7 days) in nonneutropenic patients who are clinically stable, have isolates susceptible to fluconazole (e.g., C. albicans), and have negative repeat blood cultures after initial antifungal treatment.

Amphotericin B lipid complex: 5 mg/kg once daily.

Amphotericin B liposomal: 3–5 mg/kg once daily.

IDSA recommends that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.

Treatment of Chronic Disseminated (Hepatosplenic) Candidiasis

Amphotericin B (a lipid formulation): 3–5 mg/kg daily for several weeks followed by oral fluconazole. Continue antifungal treatment until lesions resolve on repeat imaging (usually several months).

Treatment of Candida Cardiovascular Infections

Amphotericin B (a lipid formulation) for endocarditis (native or prosthetic valve) or implantable cardiac device infections: 3–5 mg/kg daily (with or without oral flucytosine). If infection caused by fluconazole-susceptible Candida, consider transitioning to oral fluconazole after patient is stabilized and Candida cleared from bloodstream.

Treatment of Esophageal Candidiasis†

Conventional amphotericin B in adults who cannot tolerate oral therapy or have fluconazole-refractory infections: 0.3–0.7 mg/kg daily.

Conventional amphotericin B in HIV-infected or other adults: 0.6 mg/kg daily for 14–21 days.

Amphotericin B (a lipid formulation) in HIV-infected adults: 3–4 mg/kg daily for 14–21 days.

Treatment of Severe or Refractory Oropharyngeal Candidiasis†

Conventional amphotericin B: 0.3 mg/kg daily.

Treatment of Symptomatic Cystitis, Pyelonephritis, or Fungus Balls

Conventional amphotericin B for symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata, C. krusei): 0.3–0.6 mg/kg daily for 1–7 days.

Conventional amphotericin B for pyelonephritis caused by fluconazole-resistant Candida: 0.3–0.6 mg/kg daily for 1–7 days (with or without oral flucytosine).

Conventional amphotericin B for urinary tract infections associated with fungus balls: 0.3–0.6 mg/kg daily for 1–7 days.

Bladder Irrigation^†

Conventional amphotericin B bladder irrigation^† for treatment of symptomatic cystitis caused by fluconazole-resistant Candida (e.g., C. glabrata, C. krusei): IDSA recommends 50-mg/L solution in sterile water for a duration of 5 days.

Conventional amphotericin B bladder irrigation^† for urinary tract infections associated with fungus balls: IDSA recommends 25–50 mg in 200–500 mL of sterile water given through nephrostomy tubes (if present).

Treatment of Candida Endophthalmitis†

Amphotericin B liposomal in patients with fluconazole- and voriconazole-resistant Candida: 3–5 mg/kg daily (with or without oral flucytosine). In patients with macular involvement, intravitreal^† administration of conventional IV amphotericin B also recommended to ensure prompt high levels of antifungal activity.

Treatment of Invasive Candida auris Infections

Amphotericin B (a lipid formulation): CDC recommends 3–5 mg/kg daily.

Coccidioidomycosis

Treatment of Coccidioidomycosis (Nonmeningeal)

Conventional amphotericin B in adults with diffuse pneumonia or disseminated coccidioidomycosis: 0.5–1.5 mg/kg daily.

Conventional amphotericin B in HIV-infected adults with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 0.7–1 mg/kg daily.

Amphotericin B (a lipid formulation) in HIV-infected adults with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 4–6 mg/kg daily.

HIV-infected adults who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole to prevent relapse or recurrence.

Cryptococcosis

Treatment of Cryptococcosis (Nonmeningeal)

Conventional amphotericin B: 0.7–1 mg/kg daily (with or without oral flucytosine) has been used.

Amphotericin B lipid complex: Manufacturer recommends 5 mg/kg once daily.

Amphotericin B liposomal: Manufacturer recommends 3–5 mg/kg once daily.

Treatment of Cryptococcal Meningitis

Conventional amphotericin B in HIV-infected adults: Induction therapy with 0.7–1 mg/kg daily given with oral flucytosine for at least 2 weeks and until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Conventional amphotericin B in HIV-infected adults who cannot receive flucytosine: Induction therapy with 0.7–1 mg/kg daily given with oral or IV fluconazole for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral fluconazole alone for at least 8 weeks. Alternatively, if necessary, IDSA states that 0.7–1 mg/kg daily can be given alone for 4–6 weeks for induction therapy followed by usual consolidation therapy.

Conventional amphotericin B in immunocompetent adults who do not have HIV infection and are not transplant recipients: Induction therapy with 0.7–1 mg/kg daily given with oral flucytosine for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole alone for 8 weeks. If patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole for 8 weeks. In those who cannot receive flucytosine, induction therapy with 0.7–1 mg/kg daily alone for at least 6 weeks, then consolidation therapy with oral fluconazole alone for 8 weeks.

Amphotericin B lipid complex in HIV-infected adults: Induction therapy with 5 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks. Alternatively, if necessary, IDSA states that 5 mg/kg daily can be given alone for 4–6 weeks for induction therapy followed by usual consolidation therapy.

Amphotericin B lipid complex in organ transplant recipients with CNS cryptococcosis: Induction therapy with 5 mg/kg daily given with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole alone for 8 weeks. If flucytosine cannot be used, consider continuing induction therapy for at least 4–6 weeks before initiating consolidation therapy.

Amphotericin B lipid complex in immunocompetent adults who do not have HIV infection and are not transplant recipients: Induction therapy with 5 mg/kg daily given with oral flucytosine for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole alone for 8 weeks. If patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole alone for 8 weeks. In those who cannot receive flucytosine, induction therapy with 5 mg/kg daily alone for at least 6 weeks, then consolidation therapy with oral fluconazole given for 8 weeks.

Amphotericin B liposomal in HIV-infected adults: Manufacturer recommends 6 mg/kg once daily.

Amphotericin B liposomal in HIV-infected adults: Induction therapy with 3–4 mg/kg daily given with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.

Amphotericin B liposomal in HIV-infected adults who cannot receive flucytosine and fluconazole: Induction and consolidation therapy in a dosage of 3–6 mg/kg daily for 4–6 weeks.

Amphotericin B liposomal in adult organ transplant recipients with CNS cryptococcosis: Induction therapy with 3–4 mg/kg daily given with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole alone for 8 weeks followed by a maintenance regimen of oral fluconazole given for 6–12 months. If flucytosine cannot be used in the induction regimen, consider continuing induction therapy for at least 4–6 weeks before initiating consolidation therapy. For relapse or high fungal burden, consider amphotericin B liposomal dosage of 6 mg/kg daily.

Amphotericin B liposomal in immunocompetent adults who do not have HIV infection and are not transplant recipients: Induction therapy with 3–4 mg/kg daily given with oral flucytosine for at least 4 weeks (6 weeks in those with neurologic complications), then consolidation therapy with oral fluconazole alone for 8 weeks. If patient is immunocompetent without uncontrolled, underlying disease and is at low risk for therapeutic failure, induction regimen can be given for only 2 weeks, followed by consolidation therapy with oral fluconazole alone for 8 weeks. In those who cannot receive flucytosine, induction therapy with 3–4 mg/kg daily alone for at least 6 weeks, then consolidation therapy with oral fluconazole alone for 8 weeks.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Conventional amphotericin B in HIV-infected adults who cannot receive fluconazole: 1 mg/kg once weekly. Initiate secondary prophylaxis after the primary infection has been adequately treated.

Exserohilum Infections†

Treatment of Known or Suspected Exserohilum Infections†

Amphotericin B liposomal for treatment of CNS and/or parameningeal infections: CDC recommends 5–6 mg/kg daily. Higher dosage (7.5 mg/kg daily) may be considered if patient is not improving, but risk of nephrotoxicity is increased. Consider giving 1 L of 0.9% sodium chloride injection prior to IV infusion of amphotericin B liposomal to minimize risk of nephrotoxicity.

Amphotericin B liposomal or other lipid formulation for treatment of osteoarticular infections: CDC recommends 5 mg/kg daily.

Adequate duration of antifungal treatment unknown; prolonged treatment required based on disease severity and clinical response.

In those with severe CNS disease with complications (arachnoiditis, stroke), persistent CSF abnormalities, or underlying immunosuppression, treatment duration of 6–12 months probably necessary. In those with parameningeal infection, consider minimum duration of 3–6 months (≥6 months for more severe disease such as discitis or osteomyelitis, underlying immunosuppression, or complications not amenable to surgical treatment).

In those with osteoarticular infections, consider minimum duration of 3 months (>3 months probably necessary for severe disease, bone infections, or underlying immunosuppression).

After treatment completion, close follow-up monitoring essential in all patients to detect potential relapse.

Consult infectious disease expert and most recent CDC guidelines for information regarding management. Consult CDC website at [Web] for most recent recommendations regarding drugs of choice, dosage, and duration of treatment.

Histoplasmosis

Treatment of Histoplasmosis

Conventional amphotericin B for treatment of moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis: IDSA recommends initial regimen of 0.7–1 mg/kg daily for 1–2 weeks, followed by oral itraconazole for total duration of 12 weeks for acute pulmonary disease or at least 12 months for progressive disseminated disease.

Amphotericin B lipid complex for treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adults: CDC, NIH, and IDSA recommend initial regimen of 3 mg/kg daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.

Amphotericin B liposomal for treatment of moderately severe to severe acute pulmonary histoplasmosis: IDSA recommends initial regimen of 3–5 mg/kg daily for 1–2 weeks, followed by oral itraconazole for total duration of 12 weeks. For treatment of moderately severe to severe progressive disseminated histoplasmosis, IDSA recommends an initial regimen of 3 mg/kg daily for 1–2 weeks, followed by oral itraconazole for total duration of at least 12 months.

Amphotericin B liposomal for treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adults: CDC, NIH, and IDSA recommend initial regimen of 3 mg/kg once daily given for at least 2 weeks or until a response is obtained, then follow-up treatment with oral itraconazole for at least 12 months.

Amphotericin B liposomal for treatment of CNS histoplasmosis in HIV-infected adults or other adults: CDC, NIH, and IDSA recommend an initial regimen of 5 mg/kg once daily for 4–6 weeks and follow-up treatment with oral itraconazole given for total treatment duration of at least 12 months and until abnormal CSF findings resolve and histoplasmal antigen is undetectable.

HIV-infected adults and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent relapse or recurrence.

Paracoccidioidomycosis†

Treatment of Paracoccidioidomycosis†

Conventional amphotericin B: 0.4–0.5 mg/kg daily, although higher dosage (i.e., 1 mg/kg daily or, rarely, 1.5 mg/kg daily) has been used for treatment of rapidly progressing, potentially fatal infections. Prolonged therapy usually required. In severely ill patients, some clinicians recommend 0.7–1 mg/kg daily for initial treatment followed by oral itraconazole.

Penicilliosis†

Treatment of Penicilliosis†

Amphotericin B liposomal in HIV-infected adults with severe, acute penicilliosis: 3–5 mg/kg daily for 2 weeks, followed by oral itraconazole (200 mg twice daily) for 10 weeks.

HIV-infected adults who have been adequately treated for penicilliosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent relapse or recurrence.

Sporotrichosis

Treatment of Sporotrichosis

Conventional amphotericin B: Manufacturer states the drug has been given for up to 9 months with total treatment dose of up to 2.5 g.

Conventional amphotericin B in patients with osteoarticular sporotrichosis: 0.7–1 mg/kg daily or until a response is obtained, followed by oral itraconazole for total treatment duration of at least 12 months.

Conventional amphotericin B in patients with severe or life-threatening pulmonary or disseminated sporotrichosis: 0.7–1 mg/kg daily can be used for initial therapy, but a lipid formulation is preferred for disseminated infections.

Conventional amphotericin B in patients with meningeal sporotrichosis: 0.7–1 mg/kg daily can be used for initial therapy, but a lipid formulation is preferred.

Amphotericin B (a lipid formulation) in patients with osteoarticular sporotrichosis: 3–5 mg/kg daily or until a response is obtained, followed by oral itraconazole for total treatment duration of at least 12 months.

Amphotericin B (a lipid formulation) in patients with severe or life-threatening pulmonary or disseminated sporotrichosis: 3–5 mg/kg daily until a response is obtained, followed by oral itraconazole for total treatment duration of at least 12 months.

Amphotericin B (a lipid formulation) in patients with meningeal sporotrichosis: 5 mg/kg daily for at least 4–6 weeks, followed by oral itraconazole for total treatment duration of at least 12 months.

Zygomycosis

Treatment of Zygomycosis

Conventional amphotericin B: 1–1.5 mg/kg daily for 2–3 months. For treatment of rhinocerebral phycomycosis, manufacturer recommends total treatment dose of at least 3 g; although total treatment dose of 3–4 g can cause lasting renal impairment, manufacturer states this is a reasonable minimum dosage if there is clinical evidence of deep tissue invasion since such infections usually rapidly fatal and aggressive therapeutic approach necessary.

Amphotericin B lipid complex: 5 mg/kg once daily.

Empiric Therapy in Febrile Neutropenic Patients

IV

Conventional amphotericin B: 0.5–1 mg/kg daily has been used.

Amphotericin B lipid complex: 3–5 mg/kg daily has been used.

Amphotericin B liposomal: 3 mg/kg once daily.

Discontinue when neutropenia resolves. In those with prolonged neutropenia, IDSA suggests that empiric antifungal therapy may be discontinued after 2 weeks if patient is clinically well and no discernible lesions are found by clinical evaluation, chest radiographs, or abdominal CT scans. If patient appears ill or is at high risk, consider continuing empiric antifungal treatment throughout the neutropenic episode.

Prevention of Fungal Infections in Transplant Recipients, Cancer Patients, or Other Patients at High Risk†

IV

Conventional amphotericin B in neutropenic cancer patients or patients undergoing BMT: 0.1–0.25 mg/kg daily.

Conventional amphotericin B in high-risk patients undergoing urologic procedures: 0.3–0.6 mg/kg daily for several days before and after the procedure.

Amphotericin B liposomal for postoperative prophylaxis in liver, pancreas, or small bowel transplant recipients: 1–2 mg/kg daily for at least 7–14 days.

Amphotericin B liposomal in neutropenic patients: 2 mg/kg 3 times weekly has been used.

Leishmaniasis

Treatment of Cutaneous and Mucocutaneous Leishmaniasis

Conventional amphotericin B for cutaneous or mucosal leishmaniasis: 0.25–0.5 mg/kg daily initially; gradually increase dosage until 0.5–1 mg/kg daily reached, at which time the drug usually given on alternate days.

Conventional amphotericin B for mucosal leishmaniasis: Some experts recommend 0.5–1 mg/kg daily or every second day for 4–8 weeks.

Duration depends on the severity of disease and response to the drug, but generally is 3–12 weeks. Total treatment dose generally ranges from 1–3 g; mucocutaneous disease usually requires higher total dose than cutaneous disease.

Treatment of Cutaneous Leishmaniasis in HIV-infected Adults

Treatment of Visceral Leishmaniasis (Kala-Azar)

Amphotericin B lipid complex^†: 1–3 mg/kg once daily for 5 days has been used in patients who failed to respond to or relapsed after treatment with an antimony compound.

Amphotericin B liposomal in immunocompetent adults: Manufacturer recommends 3 mg/kg once daily on days 1–5, then 3 mg/kg once daily on days 14 and 21; a second course of the drug may be useful if the infection is not completely cleared with a single course.

Amphotericin B liposomal in immunocompromised adults: Manufacturer recommends 4 mg/kg once daily on days 1–5, then 4 mg/kg once daily on days 10, 17, 24, 31, and 38; if the parasitic infection is not completely cleared after the first course or if relapses occur, consult an expert regarding further treatment.

Various other dosage regimens of amphotericin B liposomal have been used, including a single dose of 5–7.5 mg/kg or 10 mg/kg daily given on 2 consecutive days.

Treatment of Visceral Leishmaniasis (Kala-Azar) in HIV-infected Adults

Conventional amphotericin B^†: 0.5–1 mg/kg daily for total treatment dose of 1.5–2 g.

Amphotericin B liposomal: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg. Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.

Prevention of Recurrence (Secondary Prophylaxis) of Visceral Leishmaniasis (Kala-Azar) in HIV-infected Adults†

Amphotericin B lipid complex: 3 mg/kg once every 21 days.

Amphotericin B liposomal: 4 mg/kg once every 2–4 weeks.

Initiate secondary prophylaxis after infection has been adequately treated and CD4⁺ T-cell count <200/mm³.

Consideration can be given to discontinuing secondary prophylaxis if CD4⁺ T-cell count remained >200–350/mm³ for ≥3–6 months. Some clinicians suggest continuing secondary prophylaxis against leishmaniasis indefinitely in HIV-infected individuals.

Primary Amebic Meningoencephalitis†

Treatment of Naegleria Infections†

IV and Intrathecal^†

Conventional amphotericin B: 1.5 mg/kg IV daily in 2 divided doses for 3 consecutive days, then 1 mg/kg IV once daily for 11 consecutive days has been recommended. Intrathecal^† dosage of 1.5 mg once daily for 2 days, then 1 mg every other day for 8 days recommended. If given IV and intrathecally in same patients, some clinicians recommend maximum total dosage of 1.5 mg/kg. Use in conjunction with other anti-infectives. Consultation with specialist at CDC recommended. (See Primary Amebic Meningoencephalitis under Uses.)

Prescribing Limits

Pediatric Patients

IV

Conventional amphotericin B: Do not exceed 1.5 mg/kg daily. Use lowest effective dose.

Adults

IV

Conventional amphotericin B: Do not exceed 1.5 mg/kg daily.

Cautions for Amphotericin B

Contraindications

Conventional amphotericin B, amphotericin B lipid complex, and amphotericin B liposomal contraindicated in patients hypersensitive to amphotericin B or any component in the formulations.

Warnings/Precautions

Warnings

Acute Infusion Reactions

Acute infusion reactions (fever, shaking, chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, tachypnea) may occur 1–3 hours after initiation of IV infusions of amphotericin B.

Initial doses of conventional IV amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal should be administered under close clinical observation by medically trained personnel.

Infusion reactions reported most frequently with conventional amphotericin B, but also reported with amphotericin B lipid complex and amphotericin B liposomal. Reactions are most severe and occur most frequently with initial doses; usually lessen with subsequent doses.

Most patients (50–90%) receiving conventional IV amphotericin exhibit some degree of intolerance to initial doses of the drug, even when therapy is initiated with low doses. Although these reactions become less frequent following subsequent doses or administration of the drug on alternate days, they recur if conventional IV amphotericin B therapy is interrupted and then reinstituted.

In patients receiving conventional amphotericin B, a test dose can be used. (See Dosage and Administration.)

Tolerance to conventional amphotericin B may be improved by treatment with aspirin, antipyretics (e.g., acetaminophen), antihistamines, or antiemetics. In some patients, meperidine (25–50 mg IV) may decrease duration of shaking chills and fever during IV infusion of the drug. Manufacturer states that small doses of IV corticosteroids given just prior to or during IV infusion of conventional amphotericin B may help decrease febrile reactions, but keep dosage and duration of such corticosteroid therapy to a minimum (see Specific Drugs under Interactions). Some clinicians state that a premedication regimen (e.g., acetaminophen and diphenhydramine; acetaminophen, corticosteroid, and diphenhydramine) is not routinely recommended prior to initial doses of any amphotericin B formulation, but can be administered promptly to treat a reaction if it occurs and then as pretreatment prior to subsequent doses.

Sensitivity Reactions

Hypersensitivity Reactions

Severe hypersensitivity reactions, including anaphylaxis, reported.

If a severe hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).

Because amphotericin B may be the only effective treatment available for potentially life-threatening fungal infections, use of the drug might be considered in patients with hypersensitivity if the clinician determines that the benefits of such therapy outweigh the risks. Some manufacturers state that in such situations the drug is contraindicated in those who have had severe respiratory distress or a severe anaphylactic reaction.

General Precautions

Laboratory Monitoring

Renal, hepatic, and hematologic function should be monitored in patients receiving conventional IV amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal.

Serum electrolytes (especially potassium and magnesium) and CBCs should be monitored.

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Conventional amphotericin B: Safety and efficacy not established by adequate and well-controlled studies, but the drug has been used effectively to treat systemic fungal infections in pediatric patients without unusual adverse effects. Use lowest effective dosage in pediatric patients.

Amphotericin B lipid complex: Generally well tolerated in pediatric patients; has been used for treatment of invasive fungal infections in children 3 weeks to 16 years of age without unusual adverse effects. Acute infusion reactions (fever, chills, rigors) and anaphylaxis have been reported in pediatric patients and have necessitated discontinuance of the drug.

Amphotericin B liposomal: Has been administered to pediatric patients 1 month to 16 years of age without unusual adverse effects. Safety and efficacy not established in neonates <1 month of age. Has been used in a limited number of neonates^† for treatment of severe fungal infections without unusual adverse effects.

Geriatric Use

No substantial differences in safety and efficacy of amphotericin B lipid complex or amphotericin B liposomal in patients ≥65 years of age.

Although dosage modifications usually unnecessary, carefully monitor during treatment.

Renal Impairment

Conventional amphotericin B can be nephrotoxic and should be used with caution in patients with reduced renal function

Lipid formulations (amphotericin B lipid complex, amphotericin B liposomal) appear to be associated with a lower risk of nephrotoxicity than conventional IV amphotericin B and have been used in patients with preexisting renal impairment (in most cases resulting from prior therapy with conventional IV amphotericin B).

Common Adverse Effects

Acute infusion reactions (fever, chills, headache, nausea, vomiting); nephrotoxicity; hematologic effects. Incidence may be lower with lipid formulations (amphotericin B lipid complex, amphotericin B liposomal) than with conventional amphotericin B.

Drug Interactions

Systematic drug interaction studies have not been performed to date using amphotericin B lipid complex or amphotericin B liposomal. Consider that drug interactions reported with conventional IV amphotericin B could also occur with these lipid formulations of the drug.

Nephrotoxic Drugs

Concurrent or sequential use with other nephrotoxic drugs may result in additive nephrotoxic effects and should be avoided, if possible. Monitor renal function intensely if any amphotericin B formulation is used concomitantly with a nephrotoxic agent.

Specific Drugs

Drug	Interaction	Comments
Aminoglycosides	May enhance potential for renal toxicity	Use concomitantly with great caution; intensely monitor renal function
Antifungals, azoles (fluconazole, ketoconazole, itraconazole)	In vitro evidence of antagonistic antifungal effects against Candida or Aspergillus fumigatus	Use concomitantly with caution, particularly in immunocompromised patients.
Antineoplastic agents (mechlorethamine)	May enhance potential for renal toxicity, bronchospasm, or hypotension	Use concomitantly with great caution
Cardiac glycosides	Amphotericin B-induced hypokalemia may potentiate toxicity of cardiac glycosides	If used concomitantly, closely monitor serum potassium concentrations and cardiac function
Corticosteroids	May enhance potassium depletion and predispose patient to cardiac dysfunction	Conventional amphotericin B: Avoid concomitant use unless necessary to control adverse reactions to amphotericin B; use minimum dosage and duration of corticosteroid therapy If used concomitantly with any amphotericin B formulation, closely monitor serum electrolytes and cardiac function.
Cyclosporine	May enhance potential for renal toxicity	Use concomitantly with great caution; intensely monitor renal function
Flucytosine	Synergistic antifungal activity reported Possible increased risk of flucytosine toxicity with conventional amphotericin B because of increased cellular uptake and/or decreased renal excretion of flucytosine	Use concomitantly with caution and closely monitor flucytosine concentrations and CBCs Consider initiating flucytosine with a low dosage (75–100 mg/kg daily) and adjust subsequent dosage based on serum concentrations.
Leukocyte transfusions	Administration of conventional amphotericin B during or shortly after leukocyte transfusions has been associated with acute pulmonary reactions	Use amphotericin B with caution in patients receiving leukocyte transfusions, especially those with gram-negative septicemia. Amphotericin B doses should be separated in time as much as possible from leukocyte transfusions and monitor pulmonary function
Pentamidine	May enhance potential for renal toxicity	Use concomitantly with great caution; intensely monitor renal function
Rifabutin	In vitro evidence of additive or synergistic antifungal activity against Aspergillus and Fusarium
Skeletal muscle relaxants (tubocurarine)	Amphotericin B-induced hypokalemia may enhance curariform effects of skeletal muscle relaxants	If used concomitantly, closely monitor serum potassium concentrations
Zidovudine	Concomitant use in animals resulted in increased incidence of myelotoxicity and nephrotoxicity	Clinical importance unclear; closely monitor renal and hematologic function if used concomitantly

Amphotericin B Pharmacokinetics

The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal. Pharmacokinetic parameters reported for one formulation should not be used to predict pharmacokinetics of any other formulation.

Absorption

Bioavailability

In general, usual dosages of amphotericin B lipid complex result in lower serum concentrations and greater volumes of distribution than those reported for conventional amphotericin B.

Plasma concentrations attained with amphotericin B liposomal generally are higher and the volume of distribution is lower than those reported for conventional amphotericin B.

Distribution

Extent

Information on distribution of amphotericin B is limited. Detected in inflamed pleural fluid, peritoneum, aqueous humor, and synovium. Penetration into vitreous humor is low.

Only low concentrations distributed into CSF. Has been administered intrathecally^†.

Low concentrations attained in amniotic fluid.

Not known whether distributed into milk.

Plasma Protein Binding

>90% bound to plasma proteins.

Elimination

Metabolism

Metabolic fate has not been fully elucidated.

Elimination Route

Conventional amphotericin B is eliminated very slowly (over weeks to months) by the kidneys.

Not removed by hemodialysis.

Half-life

Conventional amphotericin B: Following IV administration, initial plasma half-life is approximately 24 hours. After the first 24 hours, the rate at which amphotericin B is eliminated decreases and an elimination half-life of approximately 15 days has been reported.

Amphotericin B lipid complex: Terminal elimination half-life is 173 hours.

Amphotericin B liposomal: Mean terminal elimination half-life is 100–153 hours.

Stability

Storage

Parenteral

Powder for IV Infusion (Conventional Amphotericin B)

2–8°C; protect from light.

Following reconstitution with sterile water for injection, colloidal solution containing 5 mg/mL is stable for 24 hours at room temperature or 1 week at 2–8°C; protect from light.

After further dilution in 5% dextrose injection to concentration ≤0.1 mg/mL, use promptly and protect from light during IV infusion.

Powder for IV Infusion (Amphotericin B Liposomal)

≤25°C.

Following reconstitution with sterile water for injection, solutions containing 4 mg/mL may be stored for up to 24 hours at 2–8°C; do not freeze.

Initiate IV infusions within 6 hours after dilution in 5% dextrose injection; discard any partially used vials.

Suspension Concentrate for IV Infusion (Amphotericin B Lipid Complex)

2–8°C; protect from light.

Following dilution in 5% dextrose injection, stable for up to 48 hours at 2–8°C and for an additional 6 hours at room temperature. Do not freeze; discard any unused solution.

Compatibility

Parenteral

Solution Compatibility (Conventional Amphotericin B)HID

Compatible
Dextrose 5, 10, or 20% in water
Incompatible
Amino acids 4.25%, dextrose 25%
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% in sodium chloride 0.9%
Fat emulsion 10 and 20%, IV
Fat emulsion 20%, IV
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility (Conventional Amphotericin B)

Admixture CompatibilityHID
Compatible
Fluconazole
Heparin sodium
Hydrocortisone sodium succinate
Sodium bicarbonate
Incompatible
Amikacin sulfate
Calcium chloride
Calcium gluconate
Chlorpromazine HCl
Ciprofloxacin
Diphenhydramine HCl
Dopamine HCl
Edetate calcium disodium
Gentamicin sulfate
Magnesium sulfate
Meropenem
Methyldopate HCl
Penicillin G potassium
Penicillin G sodium
Polymyxin B sulfate
Potassium chloride
Prochlorperazine mesylate
Ranitidine HCl
Streptomycin sulfate
Verapamil HCl

Y-Site CompatibilityHID
Compatible
Aldesleukin
Amiodarone HCl
Diltiazem HCl
Tacrolimus
Teniposide
Thiotepa
Zidovudine
Incompatible
Allopurinol sodium
Amifostine
Anidulafungin
Aztreonam
Bivalirudin
Caspofungin acetate
Ceftaroline fosamil
Dexmedetomidine HCl
Docetaxel
Doxorubicin HCl liposome injection
Enalaprilat
Etoposide phosphate
Fenoldopam mesylate
Filgrastim
Fluconazole
Fludarabine phosphate
Foscarnet sodium
Gemcitabine HCl
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Linezolid
Melphalan HCl
Meropenem
Ondansetron HCl
Oritavancin diphosphate
Paclitaxel
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Propofol
Quinupristin-dalfopristin
Telavancin HCl
Tigecycline
Vinorelbine tartrate
Variable
Cisatracurium besylate
Doripenem
Remifentanil HCl
Sargramostim

Solution Compatibility (Lipid Complex)HID

Compatible
Dextrose 5% in water

Drug Compatibility (Lipid Complex)

Y-Site CompatibilityHID
Compatible
Anidulafungin
Telavancin HCl
Incompatible
Caspofungin acetate
Tigecycline
Variable
Doripenem

Solution Compatibility (Liposomal)HID

Compatible
Dextrose 5% in water

Drug Compatibility (Liposomal)

Y-Site CompatibilityHID
Compatible
Anidulafungin
Defibrotide sodium
Incompatible
Caspofungin acetate
Telavancin HCl
Variable
Doripenem

Actions and Spectrum

Antifungal antibiotic produced by Streptomyces nodosus.
Commercially available as amphotericin B formulated with sodium desoxycholate (conventional amphotericin B), amphotericin B lipid complex (lipid formulation), and amphotericin B liposomal (lipid formulation). The lipid formulations contain lipid-based drug delivery systems that may improve the toxicity profile of amphotericin B, but also can affect pharmacokinetics and functional properties of the drug.
Amphotericin B lipid complex consists of a 1:1 molar ratio of amphotericin B complexed to a phospholipid vehicle composed of a 7:3 molar ratio of L-α-dimyristoylphosphatidylcholine (DMPC) to L-α-dimyristoylphosphatidylglycerol (DMPG).
Amphotericin B liposomal contains amphotericin B intercalated into a unilamellar bilayer liposomal membrane composed of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, distearoylphosphatidylglycerol, and α-tocopherol.
Amphotericin B usually fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms.
Binds to sterols (e.g., ergosterol) in cell membranes of susceptible fungi. As a result, cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs. Cell death occurs in part as a result of permeability changes; in some fungi, other mechanisms also may be involved.
Active against most pathogenic fungi, including yeasts, and also active against some protozoa. Inactive against bacteria, rickettsiae, and viruses.
Candida: Active in vitro against most Candida, including C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. May be active against some strains of C. lusitaniae, but other strains are resistant.
Other fungi: Active against Aspergillus fumigatus, A. flavus, Blastomyces dermatitidis, Coccidioides immitis, C. posadasii, Cryptococcus neoformans, C. gattii, Exophiala castellanii, E. spinifera, Histoplasma capsulatum, Rhodotorula, and Sporothrix schenckii. Active in vitro against Exserohilum rostratum. Some strains of Fusarium and Penicillium marneffei are inhibited in vitro by amphotericin B.
Zygomycetes: Active against Absidia, Mucor, Rhizopus, Rhizomucor, Apophysomyces elegans, and Cunninghamella. Also active against Conidiobolus coronatus and some Basidiobolus, including B. ranarum, but resistance also reported.
Protozoa: Active in vitro and in vivo against Leishmania braziliensis, L. mexicana, L. donovani, and L. tropica. Active against antimony-resistant Leishmania. Also active in vitro and possibly in vivo against Naegleria, particularly N. fowleri. Only limited and variable activity against Acanthamoeba castellanii and A. polyphaga.
Fungi resistant to conventional amphotericin B also may be resistant to amphotericin B lipid complex and amphotericin B liposomal.

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Amphotericin B
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	50 mg*	Amphotericin B for Injection

Amphotericin B Lipid Complex
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injectable suspension concentrate, for IV infusion	5 mg (of amphotericin B) per mL (100 mg)	Abelcet	Sigma-Tau

Amphotericin B Liposomal
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	50 mg (of amphotericin B)	AmBisome	Astellas

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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Drug Status

Availability Prescription only Rx

Pregnancy & Lactation Risk data available

CSA Schedule* Not a controlled drug N/A

Approval History Drug history at FDA

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