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.^{201 202 417}

Uses for Amphotericin B

Aspergillosis

Treatment of invasive aspergillosis caused by Aspergillus.^{201 207 211 219 230 231 232 235 236 237 238 239 240 241 242 243 244 248 268 269 288 292 396 379 417 420 423 436}

IDSA and others consider voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients, including HIV-infected patients.^{423 436 440} IV amphotericin B liposomal or isavuconazonium sulfate (prodrug of isavuconazole) are the preferred alternatives for primary treatment;⁴²³ IV amphotericin B lipid complex is another alternative.⁴²³

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.⁴²³

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.⁴²³

For HIV-infected adults and adolescents with invasive aspergillosis, CDC, NIH, and IDSA recommend voriconazole as drug of choice;⁴⁴⁰ IV amphotericin B (conventional or lipid formulation), IV echinocandins (anidulafungin, caspofungin, micafungin), and oral posaconazole are alternatives.⁴⁴⁰

Consult current IDSA clinical practice guidelines available at [Web]⁴²³ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]^{440 441} for additional information on management of aspergillosis.

Blastomycosis

Treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis.^{211 267 269 288 292 319 320 321 322 417 424 436 448} A drug of choice.^{227 267 283 292 319 320 424 436 448}

IV amphotericin B is preferred for initial treatment of severe blastomycosis, especially infections involving the CNS,^{269 288 292 319 320 321 322 424 436 448} and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.^{267 424} 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.^{291 424 436}

Either conventional IV amphotericin B or a lipid formulation can be used for initial treatment of blastomycosis.⁴²⁴ 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.^{424 448}

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of blastomycosis.⁴²⁴

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.^{126 211 222 223 224 225 248 254 283 292 417 436} Also used for treatment of certain severe or refractory mucocutaneous Candida infections^{† [off-label]}.^{425 436 440}

Generally effective against infections caused by C. albicans, C. glabrata, C. krusei, C. parapsilosis, or C. tropicalis.^{223 254 425} A drug of choice for many infections caused by fluconazole-resistant Candida.⁴²⁵

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;⁴²⁵ 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.⁴²⁵ 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.⁴²⁵ 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.⁴²⁵

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.⁴²⁵ Fluconazole is an alternative in those who are not critically ill and have had no prior exposure to azole antifungals;⁴²⁵ also can be used for step-down therapy in clinically stable patients who have fluconazole-susceptible isolates and documented bloodstream clearance.⁴²⁵ 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.⁴²⁵ An echinocandin, amphotericin B (a lipid formulation), or voriconazole recommended for infections caused by C. krusei.⁴²⁵

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.⁴²⁵

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.⁴²⁵ Remove infected CNS devices (e.g., ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, biopolymer wafers that deliver chemotherapy) if possible.⁴²⁵ If a ventricular device cannot be removed, IDSA states conventional amphotericin B can administered through the device.⁴²⁵ Conventional amphotericin B has been given intrathecally^{† [off-label]} as an adjunct to systemic antifungal for treatment of Candida meningitis.^{126 211 455}

For treatment of neonatal candidiasis, including CNS infections, conventional IV amphotericin B usually is the drug of choice.^{292 425} 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.^{292 425} IDSA and AAP state that fluconazole can be considered for step-down treatment after initial response obtained with IV amphotericin B.^{292 425} 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.^{292 425} 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.^{292 425}

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.⁴²⁵ 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.⁴²⁵

Mucocutaneous or noninvasive Candida infections (e.g., oropharyngeal, esophageal, or vaginal candidiasis) usually can be adequately treated with an appropriate oral or topical antifungal.^{147 269 283 425 436} 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.^{292 425 436} Also has been recommended as an alternative for treatment of esophageal candidiasis^† in patients who cannot tolerate oral therapy.^{425 440}

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).⁴²⁵ If treatment is indicated, fluconazole usually drug of choice for symptomatic cystitis, pyelonephritis, or fungus balls likely to be caused by fluconazole-susceptible Candida.⁴²⁵ 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.⁴²⁵

Conventional amphotericin B has been administered by bladder irrigation^† for treatment of candiduria (funguria),^{126 211 232 251 260 262 292 293 425 433 434 435 466 467 468 469 470 471 472 473 474} but such therapy is controversial.^{292 434 467 468 469 471 472 473 474} 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,⁴²⁵

Treatment of endophthalmitis^† caused by Candida.⁴²⁵ 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;⁴²⁵ fluconazole is an acceptable alternative for less severe endophthalmitis.⁴²⁵ In those with macular involvement, intravitreal^† administration of conventional amphotericin B also recommended to ensure prompt high levels of antifungal activity.⁴²⁵

Treatment of infections caused by C. auris, an emerging pathogen associated with potentially fatal candidemia or other invasive infections.^{504 505 506 507 508 509 510} If C. auris infection suspected, immediately contact state or local public health authorities and the CDC (candidaauris@cdc.gov) for guidance.⁵¹⁰ Consult interim recommendations and most recent information from CDC available at [Web] for additional information on diagnosis and management of C. auris infections.⁵¹⁰

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁵ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]^{440 441} for additional information on management of candidemia and other candida infections.

Coccidioidomycosis

Treatment of coccidioidomycosis caused by Coccidioides immitis or C. posadasii.^{126 248 269 285 288 292 385 394 396 417 436 440}

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.⁴²⁶ 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.⁴²⁶ 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).^{426 440 441}

For initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis, an oral azole (fluconazole or itraconazole) usually recommended.⁴²⁶ 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).^{292 426}

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.^{440 441} 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.^{440 441} 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.^{440 441}

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;^{292 426 440 441} other oral azoles (itraconazole, posaconazole, voriconazole) considered alternatives in adults and adolescents.^{426 440} 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.^{292 426 440 441} Consultation with an expert recommended.^{292 440 441}

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.^{440 441} Secondary prophylaxis with oral fluconazole or oral itraconazole also necessary in any other individual treated for coccidioidal meningitis.^{292 426}

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁶ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]^{440 441} for additional information on management of coccidioidomycosis.

Cryptococcosis

Treatment of infections caused by Cryptococcus neoformans.^{126 145 153 158 162 169 170 177 182 183 184 188 189 196 197 201 202 211 213 214 215 216 220 230 231 269 292 393 417 427 436 440} A drug of choice, especially for initial treatment of meningitis.^{126 145 153 158 162 169 170 177 182 183 184 196 197 211 213 214 269 292 393 427 436 440 441} Because of reported in vitro and in vivo synergism, usually used in conjunction with flucytosine for initial treatment,^{197 211 213 214 292 346 427 440} including in HIV-infected patients.^{145 169 172 182 183 185 192 292 427 440}

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.^{436 440 441} Can use conventional IV amphotericin B if cost is an issue and risk of renal dysfunction is low.⁴⁴⁰ 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.^{440 441}

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.^{427 436 440 441}

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.⁴⁴⁰

Alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.^{427 440} IDSA states that use of intrathecal^† or intraventricular^† conventional amphotericin B in the treatment of cryptococcal meningitis generally is discouraged and rarely necessary.⁴²⁷

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.⁴²⁷ Induction regimen should be continued for at least 4–6 weeks if flucytosine isn't included.⁴²⁷ Conventional amphotericin B not usually recommended for first-line treatment of cryptococcosis in transplant recipients because of the risk of nephrotoxicity.⁴²⁷

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.⁴²⁷

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.⁴²⁷ 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.^{427 440 441}

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.^{427 440 441} Oral itraconazole is an alternative in those who cannot tolerate fluconazole, but may be less effective than fluconazole in preventing relapse of cryptococcosis.^{427 440 441} 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.⁴²⁷

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.^{427 440}

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁷ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]^{440 441} for additional information on management of cryptococcosis.

Exserohilum Infections

Treatment of infections known or suspected to be caused by Exserohilum rostratum^†.^{476 477 487 489 490 491 492}

Exserohilum, a common mold found in soil and on plants (especially grasses),^{477 478 481 482} is rarely involved in human infections.^{478 480 481 482 487} E. rostratum has caused cutaneous and subcutaneous infections or keratitis, typically from skin or eye trauma;^{478 480 481 482 487} also has rarely caused more invasive or life-threatening infections (e.g., sinuses, heart, lungs, bones), usually in immunocompromised individuals.^{478 480 481 482 487} Exserohilum infections cannot be transmitted person-to-person.⁴⁷⁸

Although data limited and clinical relevance of in vitro testing remains uncertain,^{477 480} Exserohilum is inhibited in vitro by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B;^{477 480 481 482 489} echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity^{480 481 482} and fluconazole has poor in vitro activity against the fungus.⁴⁸¹

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]).^{477 478 488 490 491}

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.⁴⁷⁷ Majority of initial cases involved fungal meningitis (some with stroke);^{477 483 486 488 490 491 492} subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess).^{477 483 486 491} 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).^{477 483 486} Some localized infections occurred in patients with or without a diagnosis of fungal meningitis.⁴⁸³

Consultation with an infectious disease expert recommended to assist with diagnosis, management, and follow-up, which may be complex and prolonged.⁴⁷⁷ Clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636.⁴⁷⁷

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.^{477 483 486} CDC recommends routine laboratory and microbiologic tests, including bacterial and fungal cultures, as necessary;⁴⁷⁷ consider MRI evaluation if clinically warranted.^{483 486}

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.⁴⁷⁷ 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.⁴⁷⁷ IV amphotericin B liposomal also recommended as an alternative in patients unable to tolerate voriconazole.⁴⁷⁷

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.⁴⁷⁷ 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.⁴⁷⁷ A lipid formulation of IV amphotericin B, posaconazole, or itraconazole recommended as alternatives in patients who cannot tolerate voriconazole;⁴⁷⁷ expert consultation advised when making decisions regarding alternative regimens.⁴⁷⁷

Adequate duration of antifungal treatment for infections associated with contaminated corticosteroid injections not known, but prolonged therapy (at least 3–6 months) required.⁴⁷⁷ (See Exserohilum Infections under Dosage and Administration.) Close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.⁴⁷⁷

Consult CDC website at [Web] for most recent information regarding diagnosis and treatment of these infections.⁴⁷⁷

Fusarium Infections

Treatment of serious fungal infections caused by Fusarium.^{57 436} A drug of choice.^{57 436}

Select most appropriate antifungal based on in vitro susceptibility testing.⁵⁷ Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides;⁵⁷ either voriconazole or amphotericin B recommended for other Fusarium infections.⁵⁷ Consider concomitant use of amphotericin B and voriconazole in patients with severe infections or immunosuppression.⁴³⁶

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum.^{126 269 288 292 417 428 436}

IV amphotericin B and oral itraconazole are the drugs of choice for treatment of histoplasmosis, including in HIV-infected individuals.^{227 248 269 283 292 318 436 440 441} IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients (e.g., those with HIV infection).^{126 197 227 269 283 288 292 318 428 436} 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.^{227 283 288 318 428 436 440 441}

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.⁴⁴⁰ Alternatively, if necessary because of cost or tolerability, IV amphotericin B lipid complex can be used.⁴⁴⁰

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;⁴⁴¹ conventional IV amphotericin B can be used as an alternative to the lipid formulation for initial treatment in these children.⁴⁴¹ 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.^{428 441}

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.^{428 440 441} Amphotericin B liposomal generally preferred for treatment of CNS histoplasmosis^{428 440 441} because higher CSF concentrations may be obtained than with some other amphotericin B formulations.^{428 441}

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.^{428 440 441}

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁸ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]^{440 441} for additional information on management of histoplasmosis.

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis^† (South American blastomycosis) caused by Paracoccidioides brasiliensis.^{126 221 282 288 292 436}

IV amphotericin B is drug of choice for initial treatment of severe paracoccidioidomycosis.^{126 221 282 292 436} 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.^{126 292}

Penicilliosis

Treatment of penicilliosis^† caused by Penicillium marneffei.^{406 407 408 410 440}

For treatment of severe or disseminated P. marneffei infections, an initial regimen of IV amphotericin B followed by oral itraconazole recommended.^{406 407 410 440} Oral itraconazole can be used alone for treatment of mild infections.⁴⁴⁰

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.⁴⁴⁰ Voriconazole is an alternative, and may be used in those who do not respond to amphotericin B followed by itraconazole.⁴⁴⁰

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.^{407 408 440}

Consult current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ for additional information on management of penicilliosis.

Sporotrichosis

Treatment of disseminated, pulmonary, osteoarticular, and meningeal sporotrichosis caused by Sporothrix schenckii.^{126 211 269 288 289 291 292 417 429 436}

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.^{126 288 289 291 429 436} 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.^{288 289 291 429 436}

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.^{429 436}

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁹ 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.^{126 231 232 269 324 366 367 396 384 417 465}

Drug of choice for zygomycosis.^{269 324} However, severe cases of GI basidiobolomycosis caused by Basidiobolus ranarum may not respond to amphotericin B.^{413 414 415 416} GI basidiobolomycosis has been successfully treated with oral itraconazole after partial surgical resection of the GI tract.^{413 415 416}

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.^{126 195 202 248 252 273 277 290 344 372 373 374 376 422 452}

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;⁴²² lipid formulations of amphotericin B or other antifungals (e.g., caspofungin, voriconazole) also have been used.⁴²²

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.⁴²² Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also advised.⁴²²

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^†.^{126 211 249 274 277 286 287 358 371 372 375 422}

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.⁴²⁵ Risk of invasive candidiasis after other solid organ transplants (e.g., kidney, heart) appears to be too low to warrant routine antifungal prophylaxis.⁴²⁵

Conventional amphotericin B,^{211 243 261 276 286 287 460 463} amphotericin B lipid complex,^{423 460 461} and amphotericin B liposomal^{460 462 464} 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.^{102 103 104 105 106 107 108 109 126 269 271 381 417 430 442 443} 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;^{271 381 442} amphotericin B is an additional drug of choice for mucosal infections.^{271 381 442 443}

Treatment of visceral leishmaniasis (also known as kala-azar).^{108 115 116 117 126 187 202 247 253 382 383 404 430 442 443 444} 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;^{108 117 246 271 384 442 443 444} amphotericin B (conventional formulation) is considered an alternative.^{126 257 271 442 443}

Leishmaniasis is caused by >15–20 different Leishmania species that are transmitted to humans by bite of infected sand flies;^{108 430 493 494 495 499} also can be transmitted via blood (e.g., blood transfusions, needles shared by IV drug abusers) and perinatally from mother to infant.^{108 430 493 499} In Eastern Hemisphere (Old World), leishmaniasis found most frequently in parts of Asia, the Middle East, Africa, and southern Europe;⁴⁹⁹ in Western Hemisphere (New World), found most frequently in Mexico and Central and South America and reported occasionally in Texas and Oklahoma.⁴⁹⁹ Leishmaniasis reported in short-term travelers to endemic areas and in immigrants and expatriates from such areas;^{108 494 495 499} also reported in US military personnel and contract workers serving or working in endemic areas (e.g., Iraq, Afghanistan).^{108 499}

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).^{108 430 493 494 495 496 497} 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).^{108 430 493 494 495 497 499} No single treatment approach is appropriate for all possible clinical presentations.^{108 430} Consultation with clinicians experienced in management of leishmaniasis recommended.^{430 493 499}

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.⁴⁴⁰ Possible alternatives include miltefosine, topical paromomycin (not available in the US), intralesional pentavalent antimony (not available in the US), or local heat therapy.⁴⁴⁰

For HIV-infected adults and adolescents with visceral leishmaniasis, CDC, NIH, and IDSA recommend amphotericin B liposomal as the drug of choice for treatment;⁴⁴⁰ 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.⁴⁴⁰

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/mm³.⁴⁴⁰ 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.⁴⁴⁰ 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).⁴⁴⁰ 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.²⁰²

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.⁵⁰⁰ Contact CDC Drug Service at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in US.⁵⁰⁰

Primary Amebic Meningoencephalitis

Treatment of primary amebic meningoencephalitis caused by Naegleria fowleri^†, a free-living ameba.^{119 126 292 442 511 512 513}

CNS infections caused by free-living ameba associated with high mortality rate;^{292 511 512 513} early diagnosis and aggressive treatment may increase chance of survival.^{292 511 512 513} Although data limited, most reported cases of N. fowleri have been treated empirically with multiple-drug regimens.^{511 512 513} 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).^{292 442 511 512 513}

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.⁵¹¹ 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.^{442 511}

For assistance with diagnosis or treatment of suspected free-living ameba infections, contact CDC Emergency Operations Center at 770-488-7100.⁵¹¹

Amphotericin B Dosage and Administration

Administration

Administer conventional amphotericin B,⁴¹⁷ amphotericin B lipid complex,²⁰¹ and amphotericin B liposomal by IV infusion. (See Acute Infusion Reactions under Cautions.)²⁰²

Conventional amphotericin B also has been given intra-articularly^†,⁴⁵⁶ intrapleurally^†,⁴⁷⁵ intrathecally^†,^{126 211 426 440 441 455 457} by nasal instillation^† or nebulization^†,^{211 243 261 276 286 287 460 463} and by bladder irrigation^†.^{126 211 232 251 260 262 292 293 425 432 433 434 435 466 467 468 469 470 471 472 473 474} Amphotericin B lipid complex^{423 460 461} and amphotericin B liposomal^{460 462 464} 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.⁴¹⁷

Reconstitute 50-mg vial by adding 10 mL of sterile water for injection (without bacteriostatic agent) to provide a solution containing 5 mg/mL.⁴¹⁷ Add sterile water diluent rapidly to the vial using a sterile syringe and 20-gauge needle;⁴¹⁷ immediately shake vial until colloidal dispersion is clear.⁴¹⁷

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).⁴¹⁷ 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.⁴¹⁷

Rate of Administration

Administer conventional amphotericin B by IV infusion slowly over a period of approximately 2–6 hours, depending on dose.^{345 360 417}

IV infusions given over 1–2 hours may be tolerated in some patients,^{345 346 359 360 361 362} 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.^{264 359 360 362 417}

An inline membrane filter may be used;⁴¹⁷ to ensure passage of amphotericin B colloidal dispersion, the mean pore diameter of the filter should not be <1 µm.⁴¹⁷

IV Administration of Amphotericin B Lipid Complex (Abelcet)

Dilution

Amphotericin B lipid complex suspension concentrate must be diluted prior to administration.²⁰¹

Dilute in 5% dextrose injection to a concentration of 1 mg/mL according to the manufacturer's directions;²⁰¹ a concentration of 2 mg/mL may be appropriate for pediatric patients and patients with cardiovascular disease.²⁰¹

Do not use solutions containing sodium chloride or bacteriostatic agents;²⁰² do not mix with other drugs or with electrolytes.²⁰²

Prior to administration, shake IV container of diluted drug until contents are thoroughly mixed;²⁰¹ shake infusion container every 2 hours if infusion time is >2 hours.²⁰¹

Administer using a separate infusion line;²⁰¹ if an existing IV line is used, flush with 5% dextrose injection before amphotericin B lipid complex is infused.²⁰¹

Do not use an inline membrane filter during administration of amphotericin B lipid complex.²⁰¹

Rate of Administration

Administer amphotericin B lipid complex by IV infusion at a rate of 2.5 mg/kg per hour.²⁰¹

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.²⁰² Do not use other diluents (e.g., diluents containing sodium chloride or a bacteriostatic agent) to reconstitute amphotericin B liposomal;²⁰² do not admix reconstituted solution with other drugs.²⁰²

For IV infusion, reconstituted solution should be further diluted.²⁰² Withdraw the appropriate amount of reconstituted solution into a sterile syringe and attach the 5-µm sterile, disposable filter provided by the manufacturer.²⁰² 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.²⁰² Lower concentrations (0.2–0.5 mg/mL) may be appropriate for infants and small children.²⁰²

May be infused through an in-line membrane filter, provided the mean pore diameter of the filter is ≥1 µm.²⁰²

May be administered through an existing IV line;²⁰² the line must be flushed with 5% dextrose injection prior to infusion of the antifungal.²⁰² If this is not feasible, amphotericin B liposomal must be administered through a separate line.²⁰²

Rate of Administration

Administer amphotericin B liposomal by IV infusion over a period of approximately 2 hours using a controlled infusion device.²⁰² 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.²⁰²

Dosage

Available as conventional amphotericin B (formulated with sodium desoxycholate),⁴¹⁷ amphotericin B lipid complex (Abelcet),²⁰¹ or amphotericin B liposomal (AmBisome);²⁰² dosage is expressed as amphotericin B.^{201 202 417}

Dosage varies depending on whether the drug is administered as conventional amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal.^{201 202 417} Follow dosage recommendations for the specific formulation being administered.^{201 202 417}

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.⁴¹⁷ 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.⁴¹⁷ 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).⁴¹⁷ 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.⁴¹⁷

Pediatric Patients

General Pediatric Dosage

Treatment of Invasive Fungal Infections

Conventional amphotericin B: AAP recommends 1–1.5 mg/kg once daily.²⁹² Use lowest effective dosage.⁴¹⁷

Amphotericin B lipid complex: 5 mg/kg once daily.^{201 235 292}

Amphotericin B liposomal: 3–5 mg/kg daily.²⁰²

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.⁴⁴⁰

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.⁴⁴⁰

Amphotericin B lipid complex: 5 mg/kg once daily.²⁰¹

Amphotericin B liposomal in children ≥1 month of age: 3–5 mg/kg once daily.^{202 231 232}

Optimal duration of therapy uncertain.⁴²³ IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks.⁴²³

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.⁴²⁴

Amphotericin B (a lipid formulation): IDSA recommends 3–5 mg/kg once daily, followed by oral itraconazole for total treatment duration of 12 months.⁴²⁴

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Conventional amphotericin B: 0.5–1 mg/kg daily.^{254 292 436} 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.⁴²⁵

Amphotericin B lipid complex: 5 mg/kg once daily.²⁰¹

Amphotericin B liposomal in children ≥1 month of age: 3–5 mg/kg once daily.^{202 231 232} Median duration in clinical studies has been 15–29 days;^{230 231 232 379} some Candida infections have been effectively treated with a median duration of 5–7 days.^{230 231 232}

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.⁴²⁵ If CNS involved, continue antifungal until resolution of all signs, symptoms, and CSF and radiologic abnormalities (if present).⁴²⁵

Treatment of Severe or Refractory Oropharyngeal Candidiasis†

Conventional amphotericin B in HIV-infected adolescents: 0.3 mg/kg daily.⁴²⁵

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.⁴⁴¹

Conventional amphotericin B in HIV-infected adolescents: 0.6 mg/kg daily for 14–21 days.⁴⁴⁰

Amphotericin B (a lipid formulation) in HIV-infected adolescents: 3–4 mg/kg daily for 14–21 days.⁴⁴⁰

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.⁴⁴¹

Conventional amphotericin B in HIV-infected adolescents with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 0.7–1 mg/kg daily.⁴⁴⁰

Amphotericin B (a lipid formulation) in HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis: 5 mg/kg once daily.⁴⁴¹

Amphotericin B (a lipid formulation) in HIV-infected adolescents with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 4–6 mg/kg daily.⁴⁴⁰

Continue treatment with amphotericin B (conventional or lipid formulation) until improvement occurs, then switch to follow-up treatment with oral fluconazole or oral itraconazole.^{440 441} Recommended total treatment duration is1 year.^{426 441}

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.^{440 441}

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.⁴²⁷

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).⁴⁴¹

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).⁴⁴¹ Treatment duration depends on response and site and severity of infection.⁴⁴¹

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).⁴⁴¹ Same dosage can be used without flucytosine for localized disease (e.g., isolated pulmonary disease).⁴⁴¹ Treatment duration depends on response and site and severity of infection.⁴⁴¹

Amphotericin B liposomal in children ≥1 month of age: Manufacturer recommends 3–5 mg/kg once daily.²⁰²

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).⁴⁴¹ Treatment duration depends on response and site and severity of infection.⁴⁴¹

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).⁴⁴¹ Treatment duration depends on response and site and severity of infection.⁴⁴¹

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.^{427 440 441}

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.^{427 441}

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.⁴⁴¹

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.⁴⁴⁰

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.⁴⁴⁰

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.^{427 440 441}

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.⁴⁴¹

Amphotericin B liposomal in HIV-infected children ≥1 month of age: Manufacturer recommends 6 mg/kg daily.²⁰²

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.^{427 441} Same dosage can be used in children who cannot receive flucytosine.⁴⁴¹

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.⁴⁴¹

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.⁴²⁷ 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.⁴²⁷

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.⁴⁴⁰

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.⁴⁴⁰

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.^{427 440 441}

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Conventional amphotericin B in HIV-infected adolescents who cannot receive fluconazole: 1 mg/kg once weekly.⁴²⁷ Initiate secondary prophylaxis after the primary infection has been adequately treated.⁴²⁷

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.⁴²⁸

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.⁴⁴¹

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.⁴⁴⁰

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.^{440 441}

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.^{440 441}

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.^{428 440 441}

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.⁴²⁹

Leishmaniasis

Treatment of Cutaneous and Mucocutaneous Leishmaniasis

Conventional amphotericin B for cutaneous or mucosal leishmaniasis: 0.25–0.5 mg/kg daily initially;^{102 103 104 105 109} gradually increase dosage until 0.5–1 mg/kg daily is reached,^{104 105 107 108 109 126} at which time the drug usually is given on alternate days.^{107 108 126}

Conventional amphotericin B for mucosal disease: Some clinicians recommend 0.5–1 mg/kg daily or every other day for 4–8 weeks.⁴⁴²

Duration of therapy depends on severity of disease and response to the drug, but generally is 3–12 weeks.^{102 103 105} Total treatment dose generally ranges from 1–3 g;^{102 105 106 107 108 109}

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.^{126 257} 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.⁴⁴²

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;²⁰² a second course of the drug may be useful if the infection is not completely cleared with a single course.²⁰²

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;²⁰² if the parasitic infection is not completely cleared after the first course or if relapses occur, consult an expert regarding further treatment.²⁰²

Various other dosage regimens of amphotericin B liposomal have been used, including 10 mg/kg daily given on 2 consecutive days.⁴⁴⁴

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.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

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.⁴⁴⁰

Amphotericin B lipid complex^†: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

Amphotericin B liposomal: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

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.⁴⁴⁰

Amphotericin B liposomal: 4 mg/kg once every 2–4 weeks.⁴⁴⁰

Initiate secondary prophylaxis after infection has been adequately treated.⁴⁴⁰

Consideration can be given to discontinuing secondary prophylaxis if CD4⁺ T-cell count has remained >200–350/mm³ for ≥3–6 months.⁴⁴⁰ Some clinicians suggest secondary prophylaxis against leishmaniasis be continued indefinitely in HIV-infected individuals.⁴⁴⁰

Adults

Aspergillosis

Treatment of Aspergillosis

Conventional amphotericin B: 0.5–1.5 mg/kg daily.^{211 236 243 248 268 273 279 290 346 423}

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.⁴⁴⁰

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.⁴⁴⁰

Amphotericin B lipid complex: 5 mg/kg once daily.^{201 423}

Amphotericin B liposomal: 3–5 mg/kg once daily.^{202 231 232 423} Higher dosage does not result in improved efficacy and is associated with an increased incidence of adverse effects (e.g., nephrotoxicity).^{423 459}

IDSA recommends that antifungal treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks.⁴²³

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.⁴²⁴

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.⁴²⁴

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.⁴²⁴

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.⁴²⁴

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.⁴²⁴

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Conventional amphotericin B: 0.5–1 mg/kg daily.^{223 254 307}

Amphotericin B (a lipid formulation) in nonneutropenic or neutropenic adults: IDSA recommends 3–5 mg/kg daily.⁴²⁵ 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.⁴²⁵

Amphotericin B lipid complex: 5 mg/kg once daily.²⁰¹

Amphotericin B liposomal: 3–5 mg/kg once daily.^{202 231 232}

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.⁴²⁵

Treatment of Chronic Disseminated (Hepatosplenic) Candidiasis

Amphotericin B (a lipid formulation): 3–5 mg/kg daily for several weeks followed by oral fluconazole.⁴²⁵ Continue antifungal treatment until lesions resolve on repeat imaging (usually several months).⁴²⁵

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).⁴²⁵ If infection caused by fluconazole-susceptible Candida, consider transitioning to oral fluconazole after patient is stabilized and Candida cleared from bloodstream.⁴²⁵

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.⁴²⁵

Conventional amphotericin B in HIV-infected or other adults: 0.6 mg/kg daily for 14–21 days.^{425 440}

Amphotericin B (a lipid formulation) in HIV-infected adults: 3–4 mg/kg daily for 14–21 days.⁴⁴⁰

Treatment of Severe or Refractory Oropharyngeal Candidiasis†

Conventional amphotericin B: 0.3 mg/kg daily.⁴²⁵

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.⁴²⁵

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).⁴²⁵

Conventional amphotericin B for urinary tract infections associated with fungus balls: 0.3–0.6 mg/kg daily for 1–7 days.⁴²⁵

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.⁴²⁵

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).⁴²⁵

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).⁴²⁵ In patients with macular involvement, intravitreal^† administration of conventional IV amphotericin B also recommended to ensure prompt high levels of antifungal activity.⁴²⁵

Treatment of Invasive Candida auris Infections

Amphotericin B (a lipid formulation): CDC recommends 3–5 mg/kg daily.⁵¹⁰

Coccidioidomycosis

Treatment of Coccidioidomycosis (Nonmeningeal)

Conventional amphotericin B in adults with diffuse pneumonia or disseminated coccidioidomycosis: 0.5–1.5 mg/kg daily.^{211 245 436}

Conventional amphotericin B in HIV-infected adults with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 0.7–1 mg/kg daily.⁴⁴⁰

Amphotericin B (a lipid formulation) in HIV-infected adults with diffuse pulmonary or extrathoracic disseminated coccidioidomycosis: 4–6 mg/kg daily.⁴⁴⁰

Continue treatment with amphotericin B (conventional or lipid formulation) until improvement occurs,⁴⁴⁰ then switch to follow-up treatment with oral fluconazole or oral itraconazole.⁴⁴⁰ Total treatment duration of year recommended.⁴²⁶

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.⁴⁴⁰

Cryptococcosis

Treatment of Cryptococcosis (Nonmeningeal)

Conventional amphotericin B: 0.7–1 mg/kg daily (with or without oral flucytosine) has been used.^{427 436}

Amphotericin B lipid complex: Manufacturer recommends 5 mg/kg once daily.²⁰¹

Amphotericin B liposomal: Manufacturer recommends 3–5 mg/kg once daily.²⁰²

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.^{427 440}

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.^{427 440} 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.⁴²⁷

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.⁴²⁷ 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.⁴²⁷ 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.⁴²⁷

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.^{427 440} 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.⁴²⁷

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.⁴²⁷ If flucytosine cannot be used, consider continuing induction therapy for at least 4–6 weeks before initiating consolidation therapy.⁴²⁷

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.⁴²⁷ 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.⁴²⁷ 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.⁴²⁷

Amphotericin B liposomal in HIV-infected adults: Manufacturer recommends 6 mg/kg once daily.²⁰²

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.⁴⁴⁰

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.⁴²⁷

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.⁴²⁷ If flucytosine cannot be used in the induction regimen, consider continuing induction therapy for at least 4–6 weeks before initiating consolidation therapy.⁴²⁷ For relapse or high fungal burden, consider amphotericin B liposomal dosage of 6 mg/kg daily.⁴²⁷

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.⁴²⁷ 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.⁴²⁷ 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.⁴²⁷

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Conventional amphotericin B in HIV-infected adults who cannot receive fluconazole: 1 mg/kg once weekly.⁴²⁷ Initiate secondary prophylaxis after the primary infection has been adequately treated.⁴²⁷

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.⁴⁷⁷ Higher dosage (7.5 mg/kg daily) may be considered if patient is not improving, but risk of nephrotoxicity is increased.⁴⁷⁷ Consider giving 1 L of 0.9% sodium chloride injection prior to IV infusion of amphotericin B liposomal to minimize risk of nephrotoxicity.⁴⁷⁷

Amphotericin B liposomal or other lipid formulation for treatment of osteoarticular infections: CDC recommends 5 mg/kg daily.⁴⁷⁷

Adequate duration of antifungal treatment unknown;⁴⁷⁷ prolonged treatment required based on disease severity and clinical response.⁴⁷⁷

In those with severe CNS disease with complications (arachnoiditis, stroke), persistent CSF abnormalities, or underlying immunosuppression, treatment duration of 6–12 months probably necessary.⁴⁷⁷ 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).⁴⁷⁷

In those with osteoarticular infections, consider minimum duration of 3 months (>3 months probably necessary for severe disease, bone infections, or underlying immunosuppression).⁴⁷⁷

After treatment completion, close follow-up monitoring essential in all patients to detect potential relapse.⁴⁷⁷

Consult infectious disease expert and most recent CDC guidelines for information regarding management.⁴⁷⁷ Consult CDC website at [Web] for most recent recommendations regarding drugs of choice, dosage, and duration of treatment.⁴⁷⁷

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.⁴²⁸

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.⁴⁴⁰

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.⁴²⁸ 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.⁴²⁸

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.⁴⁴⁰

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.^{428 440}

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.^{428 440}

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.²²¹ Prolonged therapy usually required.²²¹ In severely ill patients, some clinicians recommend 0.7–1 mg/kg daily for initial treatment followed by oral itraconazole.⁴³⁶

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.⁴⁴⁰

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.^{407 408 440}

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.⁴¹⁷

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.⁴²⁹

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.⁴²⁹

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.⁴²⁹

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.⁴²⁹

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.⁴²⁹

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.⁴²⁹

Zygomycosis

Treatment of Zygomycosis

Conventional amphotericin B: 1–1.5 mg/kg daily for 2–3 months.^{126 211 248} For treatment of rhinocerebral phycomycosis, manufacturer recommends total treatment dose of at least 3 g;⁴¹⁷ 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.⁴¹⁷

Amphotericin B lipid complex: 5 mg/kg once daily.²⁰¹

Empiric Therapy in Febrile Neutropenic Patients

IV

Conventional amphotericin B: 0.5–1 mg/kg daily has been used.⁴⁵²

Amphotericin B lipid complex: 3–5 mg/kg daily has been used.⁴⁵²

Amphotericin B liposomal: 3 mg/kg once daily.²⁰²

Discontinue when neutropenia resolves.⁴²² 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.⁴²² If patient appears ill or is at high risk, consider continuing empiric antifungal treatment throughout the neutropenic episode.⁴²²

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.^{126 249 277 287 375}

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.⁴²⁵

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.⁴²⁵

Amphotericin B liposomal in neutropenic patients: 2 mg/kg 3 times weekly has been used.³⁵⁸

Leishmaniasis

Treatment of Cutaneous and Mucocutaneous Leishmaniasis

Conventional amphotericin B for cutaneous or mucosal leishmaniasis: 0.25–0.5 mg/kg daily initially;^{102 103 104 105 109} gradually increase dosage until 0.5–1 mg/kg daily reached,^{104 105 107 108 109 126} at which time the drug usually given on alternate days.^{107 108 126}

Conventional amphotericin B for mucosal leishmaniasis: Some experts recommend 0.5–1 mg/kg daily or every second day for 4–8 weeks.⁴⁴²

Duration depends on the severity of disease and response to the drug, but generally is 3–12 weeks.^{102 103 105 442} Total treatment dose generally ranges from 1–3 g;^{102 105 106 107 108 109} mucocutaneous disease usually requires higher total dose than cutaneous disease.^{102 103 109}

Treatment of Cutaneous Leishmaniasis in HIV-infected Adults

Amphotericin B liposomal^†: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

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.^{126 257} Some clinicians recommend 1 mg/kg daily for 15–20 days or 1 mg/kg every second day for 8 weeks.⁴⁴²

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.²⁴⁶

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;²⁰² a second course of the drug may be useful if the infection is not completely cleared with a single course.²⁰²

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;²⁰² if the parasitic infection is not completely cleared after the first course or if relapses occur, consult an expert regarding further treatment.²⁰²

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.^{443 444}

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.⁴⁴⁰

Amphotericin B lipid complex^†: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

Amphotericin B liposomal: 2–4 mg/kg daily for total treatment dose of 20–60 mg/kg.⁴⁴⁰ Alternatively, 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 for total treatment dose of 20–60 mg/kg.⁴⁴⁰

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.⁴⁴⁰

Amphotericin B liposomal: 4 mg/kg once every 2–4 weeks.⁴⁴⁰

Initiate secondary prophylaxis after infection has been adequately treated and CD4⁺ T-cell count <200/mm³.⁴⁴⁰

Consideration can be given to discontinuing secondary prophylaxis if CD4⁺ T-cell count remained >200–350/mm³ for ≥3–6 months.⁴⁴⁰ Some clinicians suggest continuing secondary prophylaxis against leishmaniasis indefinitely in HIV-infected individuals.⁴⁴⁰

Primary Amebic Meningoencephalitis†

Treatment of Naegleria Infections†

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.⁵¹¹ Intrathecal^† dosage of 1.5 mg once daily for 2 days, then 1 mg every other day for 8 days recommended.⁵¹¹ If given IV and intrathecally in same patients, some clinicians recommend maximum total dosage of 1.5 mg/kg.⁴⁴² Use in conjunction with other anti-infectives.^{292 442 511 512 513} Consultation with specialist at CDC recommended.⁵¹¹ (See Primary Amebic Meningoencephalitis under Uses.)

Prescribing Limits

Pediatric Patients

IV

Conventional amphotericin B: Do not exceed 1.5 mg/kg daily.⁴¹⁷ Use lowest effective dose.⁴¹⁷

Adults

IV

Conventional amphotericin B: Do not exceed 1.5 mg/kg daily.⁴¹⁷

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.^{201 202 417}

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.^{201 202 207 211 264 341 417}

Initial doses of conventional IV amphotericin B,⁴¹⁷ amphotericin B lipid complex,²⁰¹ or amphotericin B liposomal²⁰² 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^{201 207} and amphotericin B liposomal.²⁰² Reactions are most severe and occur most frequently with initial doses; usually lessen with subsequent doses.^{264 341 417}

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.^{211 264 417} 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.⁴¹⁷

In patients receiving conventional amphotericin B, a test dose can be used.⁴¹⁷ (See Dosage and Administration.)

Tolerance to conventional amphotericin B may be improved by treatment with aspirin, antipyretics (e.g., acetaminophen), antihistamines, or antiemetics.^{136 201 202 211 341 417} In some patients, meperidine (25–50 mg IV) may decrease duration of shaking chills and fever during IV infusion of the drug.^{211 341 417} 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).⁴¹⁷ 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.^{341 346}

Sensitivity Reactions

Hypersensitivity Reactions

Severe hypersensitivity reactions, including anaphylaxis, reported.^{201 202}

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).^{201 202}

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.^{201 202} Some manufacturers state that in such situations the drug is contraindicated in those who have had severe respiratory distress or a severe anaphylactic reaction.^{201 202}

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.^{201 202 417}

Serum electrolytes (especially potassium and magnesium) and CBCs should be monitored.^{201 202 417}

Specific Populations

Pregnancy

Category B.^{201 202 417}

Lactation

Not known whether distributed into milk.^{201 202 417} Discontinue nursing or the drug.^{201 202 417}

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.⁴¹⁷ Use lowest effective dosage in pediatric patients.⁴¹⁷

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.^{201 398} Acute infusion reactions (fever, chills, rigors) and anaphylaxis have been reported in pediatric patients and have necessitated discontinuance of the drug.³⁹⁸

Amphotericin B liposomal: Has been administered to pediatric patients 1 month to 16 years of age without unusual adverse effects.^{202 247 404} Safety and efficacy not established in neonates <1 month of age.²⁰² Has been used in a limited number of neonates^† for treatment of severe fungal infections without unusual adverse effects.^{401 403}

Geriatric Use

No substantial differences in safety and efficacy of amphotericin B lipid complex²⁰¹ or amphotericin B liposomal²⁰² in patients ≥65 years of age.

Although dosage modifications usually unnecessary, carefully monitor during treatment.²⁰²

Renal Impairment

Conventional amphotericin B can be nephrotoxic and should be used with caution in patients with reduced renal function⁴¹⁷

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).^{201 202 207 216 219 244 265 333}

Common Adverse Effects

Acute infusion reactions (fever, chills, headache, nausea, vomiting); nephrotoxicity; hematologic effects.^{201 202 207 216 219 244 264 265 333 417} Incidence may be lower with lipid formulations (amphotericin B lipid complex, amphotericin B liposomal) than with conventional amphotericin B.^{201 202 207 216 219 244 265 333}

Drug Interactions

Systematic drug interaction studies have not been performed to date using amphotericin B lipid complex²⁰¹ or amphotericin B liposomal.²⁰² Consider that drug interactions reported with conventional IV amphotericin B could also occur with these lipid formulations of the drug.^{201 202}

Nephrotoxic Drugs

Concurrent or sequential use with other nephrotoxic drugs may result in additive nephrotoxic effects and should be avoided, if possible.^{201 202 417} Monitor renal function intensely if any amphotericin B formulation is used concomitantly with a nephrotoxic agent.^{201 202 417}

Specific Drugs

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.^{201 202 205 210 332 417} Pharmacokinetic parameters reported for one formulation should not be used to predict pharmacokinetics of any other formulation.^{201 202 205 210 332 417}

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.^{201 206 207 210 265 333}

Plasma concentrations attained with amphotericin B liposomal generally are higher and the volume of distribution is lower than those reported for conventional amphotericin B.^{202 205 209 210 269 332}

Distribution

Extent

Information on distribution of amphotericin B is limited.⁴¹⁷ Detected in inflamed pleural fluid, peritoneum, aqueous humor, and synovium.⁴¹⁷ Penetration into vitreous humor is low.⁴¹⁷

Only low concentrations distributed into CSF.⁴¹⁷ Has been administered intrathecally^†.^{126 211 426 440 441 455 457}

Low concentrations attained in amniotic fluid.⁴¹⁷

Not known whether distributed into milk.^{201 202 417}

Plasma Protein Binding

>90% bound to plasma proteins.⁴¹⁷

Elimination

Metabolism

Metabolic fate has not been fully elucidated.⁴¹⁷

Elimination Route

Conventional amphotericin B is eliminated very slowly (over weeks to months) by the kidneys.⁴¹⁷

Not removed by hemodialysis.⁴¹⁷

Half-life

Conventional amphotericin B: Following IV administration, initial plasma half-life is approximately 24 hours.⁴¹⁷ 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.⁴¹⁷

Amphotericin B lipid complex: Terminal elimination half-life is 173 hours.²⁰¹

Amphotericin B liposomal: Mean terminal elimination half-life is 100–153 hours.²⁰²

Stability

Storage

Parenteral

Powder for IV Infusion (Conventional Amphotericin B)

2–8°C;⁴¹⁷ protect from light.⁴¹⁷

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;⁴¹⁷ protect from light.⁴¹⁷

After further dilution in 5% dextrose injection to concentration ≤0.1 mg/mL, use promptly and protect from light during IV infusion.⁴¹⁷

Powder for IV Infusion (Amphotericin B Liposomal)

≤25°C.²⁰²

Following reconstitution with sterile water for injection, solutions containing 4 mg/mL may be stored for up to 24 hours at 2–8°C;²⁰² do not freeze.²⁰²

Initiate IV infusions within 6 hours after dilution in 5% dextrose injection;²⁰² discard any partially used vials.²⁰²

Suspension Concentrate for IV Infusion (Amphotericin B Lipid Complex)

2–8°C; protect from light.²⁰¹

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.²⁰¹ Do not freeze;²⁰¹ discard any unused solution.²⁰¹

Compatibility

Parenteral

Solution Compatibility (Conventional Amphotericin B)HID

Drug Compatibility (Conventional Amphotericin B)

Solution Compatibility (Lipid Complex)HID

Drug Compatibility (Lipid Complex)

Solution Compatibility (Liposomal)HID

Drug Compatibility (Liposomal)

Actions and Spectrum

• Antifungal antibiotic produced by Streptomyces nodosus.^{201 202 417}

• Commercially available as amphotericin B formulated with sodium desoxycholate (conventional amphotericin B),⁴¹⁷ amphotericin B lipid complex (lipid formulation),²⁰¹ and amphotericin B liposomal (lipid formulation).²⁰² 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.^{201 202 206 207 210 211 233 234 265 333}

• 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).²⁰¹

• Amphotericin B liposomal contains amphotericin B intercalated into a unilamellar bilayer liposomal membrane composed of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, distearoylphosphatidylglycerol, and α-tocopherol.²⁰²

• Amphotericin B usually fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms.^{308 313 417}

• Binds to sterols (e.g., ergosterol) in cell membranes of susceptible fungi.^{201 202 269 417} As a result, cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs.⁴¹⁷ Cell death occurs in part as a result of permeability changes;^{141 326 327 346 417} in some fungi, other mechanisms also may be involved.^{141 326 327 346}

• Active against most pathogenic fungi, including yeasts, and also active against some protozoa.^{312 315 339 417} Inactive against bacteria, rickettsiae, and viruses.⁴¹⁷

• Candida: Active in vitro against most Candida,^{312 385 388 389 391} including C. albicans,^{385 388 391} C. dubliniensis,³⁸⁹ C. glabrata,^{385 391} C. krusei,³⁸⁵ C. parapsilosis,^{385 391} and C. tropicalis.^{385 391 389 391} May be active against some strains of C. lusitaniae,³⁸⁶ but other strains are resistant.^{343 399 402}

• Other fungi: Active against Aspergillus fumigatus,³⁹² A. flavus,³⁹² Blastomyces dermatitidis,⁴¹⁷ Coccidioides immitis,⁴¹⁷ C. posadasii,^{446 447} Cryptococcus neoformans,^{385 391} C. gattii,⁴⁵³ Exophiala castellanii,²⁵⁸ E. spinifera,²⁵⁸ Histoplasma capsulatum,⁴¹⁷ Rhodotorula,⁴¹⁷ and Sporothrix schenckii.⁴¹⁷ Active in vitro against Exserohilum rostratum.^{480 481 482 477} Some strains of Fusarium and Penicillium marneffei are inhibited in vitro by amphotericin B.^{409 445}

• Zygomycetes: Active against Absidia,^{418 419} Mucor,^{417 418 419} Rhizopus,^{418 419} Rhizomucor,^{418 419} Apophysomyces elegans,^{368 418 419} and Cunninghamella.^{418 419} Also active against Conidiobolus coronatus⁴²¹ and some Basidiobolus, including B. ranarum,^{415 419 421} but resistance also reported.^{414 415}

• Protozoa: Active in vitro¹⁰² and in vivo^{102 103 104 105 106 107 108 109} against Leishmania braziliensis, L. mexicana,^{107 108 109 111 112 113 114} L. donovani,^{108 111 112 113 114 115 116 117} and L. tropica.^{111 114} Active against antimony-resistant Leishmania.^{107 108 109 111 112 113 114 115 116 117} Also active in vitro^{118 119 120 121 124 125} and possibly in vivo^{118 119 122 123 124} against Naegleria, particularly N. fowleri. Only limited and variable activity against Acanthamoeba castellanii and A. polyphaga.^{121 125}

• Fungi resistant to conventional amphotericin B also may be resistant to amphotericin B lipid complex and amphotericin B liposomal.^{201 202}

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.^{201 202 417}

• Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.^{201 202 417}

• Importance of advising patients of other important precautionary information.^{201 202 417} (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

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